Dna-pk inhibitors

ABSTRACT

The present invention relates to compounds useful as inhibitors of DNA-PK. The invention also provides pharmaceutically acceptable compositions comprising said compounds and methods of using the compositions in the treatment of various disease, conditions, or disorders.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds useful as inhibitors ofDNA-dependent protein kinase (DNA-PK). The invention also providespharmaceutically acceptable compositions comprising the compounds of theinvention and methods of using the compositions in the treatment ofcancer.

BACKGROUND OF THE INVENTION

Ionizing radiation (IR) induces a variety of DNA damage of which doublestrand breaks (DSBs) are the most cytotoxic. These DSBs can lead to celldeath via apoptosis and/or mitotic catastrophe if not rapidly andcompletely repaired. In addition to IR, certain chemotherapeutic agentsincluding topoisomerase II inhibitors, bleomycin, and doxorubicin alsocause DSBs. These DNA lesions trigger a complex set of signals throughthe DNA damage response network that function to repair the damaged DNAand maintain cell viability and genomic stability. In mammalian cells,the predominant repair pathway for DSBs is the Non-Homologous EndJoining Pathway (NHEJ). This pathway functions regardless of the phaseof the cell cycle and does not require a template to re-ligate thebroken DNA ends. NHEJ requires coordination of many proteins andsignaling pathways. The core NHEJ machinery consists of the Ku70/80heterodimer and the catalytic subunit of DNA-dependent protein kinase(DNA-PKcs), which together comprise the active DNA-PK enzyme complex.DNA-PKcs is a member of the phosphatidylinositol 3-kinase-related kinase(PIKK) family of serine/threonine protein kinases that also includesataxia telangiectasia mutated (ATM), ataxia telangiectasia andRad3-related (ATR), mTOR, and four PI3K isoforms. However, whileDNA-PKcs is in the same protein kinase family as ATM and ATR, theselatter kinases function to repair DNA damage through the HomologousRecombination (HR) pathway and are restricted to the S and G₂ phases ofthe cell cycle. While ATM is also recruited to sites of DSBs, ATR isrecruited to sites of single stranded DNA breaks.

NHEJ is thought to proceed through three key steps: recognition of theDSBs, DNA processing to remove non-ligatable ends or other forms ofdamage at the termini, and finally ligation of the DNA ends. Recognitionof the DSB is carried out by binding of the Ku heterodimer to the raggedDNA ends followed by recruitment of two molecules of DNA-PKcs toadjacent sides of the DSB; this serves to protect the broken terminiuntil additional processing enzymes are recruited. Recent data supportsthe hypothesis that DNA-PKcs phosphorylates the processing enzyme,Artemis, as well as itself to prepare the DNA ends for additionalprocessing. In some cases DNA polymerase may be required to synthesizenew ends prior to the ligation step. The auto-phosphorylation ofDNA-PKcs is believed to induce a conformational change that opens thecentral DNA binding cavity, releases DNA-PKcs from DNA, and facilitatesthe ultimate religation of the DNA ends.

It has been known for some time that DNA-PK^(−/−) mice arehypersensitive to the effects of IR and that some non-selective smallmolecule inhibitors of DNA-PKcs can radiosensitize a variety of tumorcell types across a broad set of genetic backgrounds. While it isexpected that inhibition of DNA-PK will radiosensitize normal cells tosome extent, this has been observed to a lesser degree than with tumorcells likely due to the fact that tumor cells possess higher basallevels of endogenous replication stress and DNA damage (oncogene-inducedreplication stress) and DNA repair mechanisms are less efficient intumor cells. Most importantly, an improved therapeutic window withgreater sparing of normal tissue will be imparted from the combinationof a DNA-PK inhibitor with recent advances in precision delivery offocused IR, including image-guide RT (IGRT) and intensity-modulated RT(IMRT).

Inhibition of DNA-PK activity induces effects in both cycling andnon-cycling cells. This is highly significant since the majority ofcells in a solid tumor are not actively replicating at any given moment,which limits the efficacy of many agents targeting the cell cycle.Equally intriguing are recent reports that suggest a strong connectionbetween inhibition of the NHEJ pathway and the ability to killtraditionally radioresistant cancer stem cells (CSCs). It has been shownin some tumor cells that DSBs in dormant CSCs predominantly activate DNArepair through the NHEJ pathway; it is believed that CSCs are usually inthe quiescent phase of the cell cycle. This may explain why half ofcancer patients may experience local or distant tumor relapse despitetreatment as current strategies are not able to effectively target CSCs.A DNA-PK inhibitor may have the ability to sensitize these potentialmetastatic progenitor cells to the effects of IR and select DSB-inducingchemotherapeutic agents.

Given the involvement of DNA-PK in DNA repair processes, an applicationof specific DNA-PK inhibitory drugs would be to act as agents that willenhance the efficacy of both cancer chemotherapy and radiotherapy.Accordingly, it would be desirable to develop compounds useful asinhibitors of DNA-PK.

SUMMARY OF THE INVENTION

It has been found that compounds of this invention, and pharmaceuticallyacceptable compositions thereof, are effective as inhibitors of DNA-PK.Accordingly, the invention features compounds having the generalformula:

or a pharmaceutically acceptable salt thereof, where each of R¹, Q, RingA, and Ring B is as defined herein.

The invention also provides pharmaceutical compositions that include acompound of formula I and a pharmaceutically acceptable carrier,adjuvant, or vehicle. These compounds and pharmaceutical compositionsare useful for treating or lessening the severity of cancer.

The compounds and compositions provided by this invention are alsouseful for the study of DNA-PK in biological and pathological phenomena;the study of intracellular signal transduction pathways mediated by suchkinases; and the comparative evaluation of new kinase inhibitors.

DETAILED DESCRIPTION OF THE INVENTION Definitions and GeneralTerminology

As used herein, the following definitions shall apply unless otherwiseindicated. For purposes of this invention, the chemical elements areidentified in accordance with the Periodic Table of the Elements, CASversion, and the Handbook of Chemistry and Physics, 75^(th) Ed. 1994.Additionally, general principles of organic chemistry are described in“Organic Chemistry,” Thomas Sorrell, University Science Books,Sausalito: 1999, and “March's Advanced Organic Chemistry,” 5^(th) Ed.,Smith, M. B. and March, J., eds. John Wiley & Sons, New York: 2001, theentire contents of which are hereby incorporated by reference.

As described herein, compounds of the invention may optionally besubstituted with one or more substituents, such as are illustratedgenerally above, or as exemplified by particular classes, subclasses,and species of the invention. It will be appreciated that the phrase“optionally substituted” is used interchangeably with the phrase“substituted or unsubstituted.” In general, the term “substituted,”whether preceded by the term “optionally” or not, refers to thereplacement of one or more hydrogen radicals in a given structure withthe radical of a specified substituent. Unless otherwise indicated, anoptionally substituted group may have a substituent at eachsubstitutable position of the group. When more than one position in agiven structure can be substituted with more than one substituentselected from a specified group, the substituent may be either the sameor different at each position.

As described herein, when the term “optionally substituted” precedes alist, said term refers to all of the subsequent substitutable groups inthat list. For example, if X is halogen; optionally substituted C₁₋₃alkyl or phenyl; X may be either optionally substituted alkyl oroptionally substituted phenyl. Likewise, if the term “optionallysubstituted” follows a list, said term also refers to all of thesubstitutable groups in the prior list unless otherwise indicated. Forexample: if X is halogen, C₁₋₃ alkyl, or phenyl, wherein X is optionallysubstituted by J^(X), then both C₁₋₃ alkyl and phenyl may be optionallysubstituted by J^(X). As is apparent to one having ordinary skill in theart, groups such as H, halogen, NO₂, CN, NH₂, OH, or OCF₃ would not beincluded because they are not substitutable groups. As is also apparentto a skilled person, a heteroaryl or heterocyclic ring containing an NHgroup can be optionally substituted by replacing the hydrogen atom withthe substituent. If a substituent radical or structure is not identifiedor defined as “optionally substituted,” the substituent radical orstructure is unsubstituted.

Combinations of substituents envisioned by this invention are preferablythose that result in the formation of stable or chemically feasiblecompounds. The term “stable,” as used herein, refers to compounds thatare not substantially altered when subjected to conditions to allow fortheir production, detection, and, preferably, their recovery,purification, and use for one or more of the purposes disclosed herein.In some embodiments, a stable compound or chemically feasible compoundis one that is not substantially altered when kept at a temperature of40° C. or less, in the absence of moisture or other chemically reactiveconditions, for at least a week.

The term “alkyl” or “alkyl group,” as used herein, means astraight-chain (i.e., unbranched) or branched, substituted orunsubstituted hydrocarbon chain that is completely saturated. Unlessotherwise specified, alkyl groups contain 1-8 carbon atoms. In someembodiments, alkyl groups contain 1-6 carbon atoms, and in yet otherembodiments, alkyl groups contain 1-4 carbon atoms (represented as “C₁₋₄alkyl”). In other embodiments, alkyl groups are characterized as “C₀₋₄alkyl” representing either a covalent bond or a C₁₋₄ alkyl chain.Examples of alkyl groups include methyl, ethyl, propyl, butyl,isopropyl, isobutyl, sec-butyl, and tert-butyl. The term “alkylene,” asused herein, represents a saturated divalent straight or branched chainhydrocarbon group and is exemplified by methylene, ethylene,isopropylene and the like. The term “alkylidene,” as used herein,represents a divalent straight chain alkyl linking group. The term“alkenyl,” as used herein, represents monovalent straight or branchedchain hydrocarbon group containing one or more carbon-carbon doublebonds. The term “alkynyl,” as used herein, represents a monovalentstraight or branched chain hydrocarbon group containing one or morecarbon-carbon triple bonds.

The term “cycloalkyl” (or “carbocycle”) refers to a monocyclic C₃-C₈hydrocarbon or bicyclic C₈-C₁₂ hydrocarbon that is completely saturatedand has a single point of attachment to the rest of the molecule, andwherein any individual ring in said bicyclic ring system has 3-7members. Suitable cycloalkyl groups include, but are not limited to,cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.

The term “heterocycle,” “heterocyclyl,” “heterocycloalkyl,” or“heterocyclic” as used herein refers to a monocyclic, bicyclic, ortricyclic ring system in which at least one ring in the system containsone or more heteroatoms, which is the same or different, and that iscompletely saturated or that contains one or more units of unsaturation,but which is not aromatic, and that has a single point of attachment tothe rest of the molecule. In some embodiments, the “heterocycle,”“heterocyclyl,” “heterocycloalkyl,” or “heterocyclic” group has three tofourteen ring members in which one or more ring members is a heteroatomindependently selected from oxygen, sulfur, nitrogen, or phosphorus, andeach ring in the system contains 3 to 8 ring members.

Examples of heterocyclic rings include, but are not limited to, thefollowing monocycles: 2-tetrahydrofuranyl, 3-tetrahydrofuranyl,2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholino,3-morpholino, 4-morpholino, 2-thiomorpholino, 3-thiomorpholino,4-thiomorpholino, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl,1-tetrahydropiperazinyl, 2-tetrahydropiperazinyl,3-tetrahydropiperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl,1-pyrazolinyl, 3-pyrazolinyl, 4-pyrazolinyl, 5-pyrazolinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,2-thiazolidinyl, 3-thiazolidinyl, 4-thiazolidinyl, 1-imidazolidinyl,2-imidazolidinyl, 4-imidazolidinyl, 5-imidazolidinyl; and the followingbicycles: 3-1H-benzimidazol-2-one, 3-(1-alkyl)-benzimidazol-2-one,indolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, benzothiolane,benzodithiane, and 1,3-dihydro-imidazol-2-one.

The term “heteroatom” means one or more of oxygen, sulfur, nitrogen, orphosphorus, including any oxidized form of nitrogen, sulfur, orphosphorus; the quaternized form of any basic nitrogen; or asubstitutable nitrogen of a heterocyclic ring, for example N (as in3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl) or NR⁺ (as inN-substituted pyrrolidinyl).

The term “unsaturated,” as used herein, means that a moiety has one ormore units of unsaturation.

The term “alkoxy,” or “thioalkyl,” as used herein, refers to an alkylgroup, as previously defined, attached to the principal carbon chainthrough an oxygen (“alkoxy”) or sulfur (“thioalkyl”) atom.

The terms “haloalkyl,” “haloalkenyl,” and “haloalkoxy” mean alkyl,alkenyl, or alkoxy, as the case may be, substituted with one or morehalogen atoms. The term “halogen” means F, Cl, Br, or I.

The term “aryl” used alone or as part of a larger moiety as in“aralkyl,” “aralkoxy,” or “aryloxyalkyl,” refers to a monocyclic,bicyclic, or tricyclic carbocyclic ring system having a total of six tofourteen ring members, wherein said ring system has a single point ofattachment to the rest of the molecule, at least one ring in the systemis aromatic and wherein each ring in the system contains 4 to 7 ringmembers. The term “aryl” may be used interchangeably with the term “arylring.” Examples of aryl rings include phenyl, naphthyl, and anthracene.

The term “heteroaryl,” used alone or as part of a larger moiety as in“heteroaralkyl,” or “heteroarylalkoxy,” refers to a monocyclic,bicyclic, and tricyclic ring system having a total of five to fourteenring members, wherein said ring system has a single point of attachmentto the rest of the molecule, at least one ring in the system isaromatic, at least one ring in the system contains one or moreheteroatoms independently selected from nitrogen, oxygen, sulfur orphosphorus, and wherein each ring in the system contains 4 to 7 ringmembers. The term “heteroaryl” may be used interchangeably with the term“heteroaryl ring” or the term “heteroaromatic.”

Further examples of heteroaryl rings include the following monocycles:2-furanyl, 3-furanyl, N-imidazolyl, 2-imidazolyl, 4-imidazolyl,5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxazolyl,4-oxazolyl, 5-oxazolyl, N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,pyridazinyl (e.g., 3-pyridazinyl), 2-thiazolyl, 4-thiazolyl,5-thiazolyl, tetrazolyl (e.g., 5-tetrazolyl), triazolyl (e.g.,2-triazolyl and 5-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g.,2-pyrazolyl), isothiazolyl, 1,2,3-oxadiazolyl, 1,2,5-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,3-triazolyl, 1,2,3-thiadiazolyl,1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrazinyl, 1,3,5-triazinyl, andthe following bicycles: benzimidazolyl, benzofuryl, benzothiophenyl,indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl,3-quinolinyl, 4-quinolinyl), and isoquinolinyl (e.g., 1-isoquinolinyl,3-isoquinolinyl, or 4-isoquinolinyl).

As described herein, a bond drawn from a substituent to the center ofone ring within a multiple-ring system (as shown below) representssubstitution of the substituent at any substitutable position in any ofthe rings within the multiple ring system. For example, Structure arepresents possible substitution in any of the positions shown inStructure b.

This also applies to multiple ring systems fused to optional ringsystems (which would be represented by dotted lines). For example, inStructure c, X is an optional substituent both for ring A and ring B.

If, however, two rings in a multiple ring system each have differentsubstituents drawn from the center of each ring, then, unless otherwisespecified, each substituent only represents substitution on the ring towhich it is attached. For example, in Structure d, Y is an optionallysubstituent for ring A only, and X is an optional substituent for ring Bonly.

The term “protecting group,” as used herein, represent those groupsintended to protect a functional group, such as, for example, analcohol, amine, carboxyl, carbonyl, etc., against undesirable reactionsduring synthetic procedures. Commonly used protecting groups aredisclosed in Greene and Wuts, Protective Groups In Organic Synthesis,3^(rd) Edition (John Wiley & Sons, New York, 1999), which isincorporated herein by reference. Examples of nitrogen protecting groupsinclude acyl, aroyl, or carbamyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl and chiral auxiliaries such as protected or unprotectedD, L or D, L-amino acids such as alanine, leucine, phenylalanine and thelike; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and thelike; carbamate groups such as benzyloxycarbonyl,p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike, arylalkyl groups such as benzyl, triphenylmethyl, benzyloxymethyland the like and silyl groups such as trimethylsilyl and the like.Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl,t-butylacetyl, alanyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc)and benzyloxycarbonyl (Cbz).

Unless otherwise depicted or stated, structures recited herein are meantto include all isomeric (e.g., enantiomeric, diastereomeric, andgeometric (or conformational)) forms of the structure; for example, theR and S configurations for each asymmetric center, (Z) and (E) doublebond isomers, and (Z) and (E) conformational isomers. Therefore, singlestereochemical isomers as well as enantiomeric, diastereomeric, andgeometric (or conformational) mixtures of the present compounds arewithin the scope of the invention. Compounds that have been drawn withstereochemical centers defined, usually through the use of a hatched (

) or bolded (

) bond, are stereochemically pure, but with the absolute stereochemistrystill undefined. Such compounds can have either the R or Sconfiguration. In those cases where the absolute configuration has beendetermined, the chiral center(s) are labeled (R) or (S) in the drawing.

Unless otherwise stated, all tautomeric forms of the compounds of theinvention are within the scope of the invention. Additionally, unlessotherwise stated, structures depicted herein are also meant to includecompounds that differ only in the presence of one or more isotopicallyenriched atoms. For example, compounds having the present structuresexcept for the replacement of hydrogen by deuterium or tritium, or thereplacement of a carbon by a ¹³C- or ¹⁴C-enriched carbon are within thescope of this invention. Such compounds are useful, for example, asanalytical tools, probes in biological assays, or as DNA-PK inhibitorswith an improved therapeutic profile.

Description of Compounds of the Invention

In one aspect, the invention features compounds having the formula:

-   or a pharmaceutically acceptable salt thereof, wherein-   Q is N or CH;-   R¹ is hydrogen, CH₃, CH₂CH₃, or R¹ and the carbon to which it is    bound form a C═CH₂ group;-   Ring A is a ring system selected from

-   R^(A1) is hydrogen, halogen, C₁₋₄alkyl, C₀₋₄alkyl-C₃₋₆cycloalkyl,    C₀₋₄alkyl-OR^(A1a), C₀₋₄alkyl-SR^(A1a), C₀₋₄alkyl-C(O)N(R^(A1a))₂,    C₀₋₄alkyl-CN, C₀₋₄alkyl-S(O)—C₁₋₄alkyl, C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl,    C₀₋₄alkyl-C(O)OR^(A1b), C₀₋₄alkyl-C(O)C₁₋₄alkyl,    C₀₋₄alkyl-N(R^(A1b))C(O)R^(A1a), C₀₋₄alkyl-N(R^(A1b))S(O)₂R^(A1a),    C₀₋₄alkyl-N(R^(A1a))₂, C₀₋₄alkyl-N(R^(A1b))(3-6    membered-cycloalkyl), C₀₋₄alkyl-N(R^(A1b))(4-6    membered-heterocyclyl), N(R^(A1b))C₂₋₄alkyl-N(R^(A1a))₂,    N(R^(A1b))C₂₋₄alkyl-OR^(A1a), N(R^(A1b))C₁₋₄alkyl-(5-10 membered    heteroaryl), N(R^(A1b))C₁₋₄alkyl-(4-6 membered heterocyclyl),    N(R^(A1b))C₂₋₄alkyl-N(R^(A1b))C(O)R^(A1a),    C₀₋₄alkyl-N(R^(A1b))C(O)C₁₋₄alkyl,    C₀₋₄alkyl-N(R^(A1b))C(O)OC₁₋₄alkyl, C₀₋₄alkyl-(phenyl),    C₀₋₄alkyl-(3-10 membered-heterocyclyl), C₀₋₄alkyl-C(O)-(4-6    membered-heterocyclyl), C₀₋₄alkyl-O—C₀₋₄alkyl-(4-6    membered-heterocyclyl), C₀₋₄alkyl-(5-6 membered-heteroaryl),    C₀₋₄alkyl-C(O)-(5-6 membered-heteroaryl), C₀₋₄alkyl-O—C₀₋₄alkyl-(5-6    membered-heteroaryl), C₀₋₄alkyl-N(R^(A1a))(4-6    membered-heterocyclyl), or C₀₋₄alkyl-N(R^(A1b))(5-6    membered-heteroaryl), wherein each of said R^(A1) heterocyclyl is a    ring system selected from aziridinyl, oxetanyl, tetrahydropyran,    tetrahydrofuranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl,    pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl,    piperazinyl, piperazinonyl, tetrahydrothiophenedioxidyl,    1,1-dioxothietanyl, 2-oxa-6-azaspiro[3.4]octanyl, or isoindolinonyl    wherein each of said R^(A1) heteroaryl is a ring system selected    from furanyl, thiophenyl, imidazolyl, benzoimidazolyl, oxazolyl,    oxadiazolyl, thiazolyl, pyrazolyl, thiadiazolyl, pyridinyl,    pyrimidinyl, pyrazinyl, triazolyl, or tetrazolyl, and wherein each    of said R^(A1) alkyl, cycloalkyl, phenyl, heterocyclyl, or    heteroaryl groups is optionally substituted with up to three F    atoms, up to two C₁₋₂alkyl groups, a C₃₋₆cycloalkyl group, a phenyl    group, a benzyl group, an alkenyl-C₀₋₂alkyl group, an    alkynyl-C₀₋₂alkyl group, up to two C₀₋₂alkyl-OR^(A1b) groups, a    C₀₋₂alkyl-N(R^(A1b))₂ group, a SC₁₋₄alkyl group, a S(O)₂C₁₋₄alkyl    group, a C(O)R^(A1b) group, a C(O)OR^(A1b) group, a C(O)N(R^(A1b))₂    group, a —CN group, or a C₄₋₆heterocyclic ring system selected from    oxetanyl, tetrahydrofuranyl, tetrahydropyran, piperidinyl, or    morpholinyl; each R^(A1a) is, independently, hydrogen, C₁₋₄alkyl,    C₃₋₆cycloalkyl, C₄₋₆heterocyclyl selected from oxetanyl,    tetrahydrofuranyl, tetrahydropyran, pyrrolidinyl, or piperidinyl,    C₃₋₆heteroaryl selected from imidazolyl, triazolyl, tetrazolyl,    pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or    pyrazinyl, or two R^(A1a) and an intervening nitrogen atom form a    3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl,    pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl,    tetrahydropyridinyl, piperazinyl, or morpholinyl, wherein each of    said R^(A1a) alkyl, cycloalkyl, heterocyclyl, or heteroaryl groups    is optionally substituted with up to three F atoms, up to two    C₁₋₂alkyl groups, a C₃₋₆cycloalkyl group, up to two    C₀₋₂alkyl-OR^(A1b) groups, a C₀₋₂alkyl-N(R^(A1b))₂ group, a    SC₁₋₄alkyl group, a C(O)R^(A1b) group, a C(O)OR^(A1b) group, a    C(O)N(R^(A1b))₂ group, or a —CN group;-   each R^(A1b) is, independently, hydrogen, C₁₋₂alkyl, or    C₃₋₄cycloalkyl;-   R^(A2) is hydrogen, C₁₋₄alkyl, C₀₋₄alkyl-C₃₋₆cycloalkyl,    C₀₋₂alkyl-(4-6 membered)heterocyclyl, C₂₋₄alkyl-OR^(A2a),    C₀₋₂alkyl-C(O)N(R^(A2a))₂, C₀₋₂alkyl-S(O)₂—C₁₋₄alkyl,    C₀₋₂alkyl-C(O)OC₁₋₄alkyl, C₀₋₂alkyl-C(O)-(4-6 membered)heterocyclyl,    wherein each of said heterocyclyl is selected from oxetanyl,    tetrahydropyran, tetrahydrofuranyl, dioxanyl, dioxolanyl,    azetidinyl, pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl,    morpholinyl, piperidinyl, piperazinyl, piperazinonyl, or    1,1-dioxothietanyl, and each of said R^(A2) groups except hydrogen    is optionally substituted with up to three F atoms, up to two    C₁₋₂alkyl groups, a C₃₋₆cycloalkyl group, an alkenyl-C₀₋₂alkyl    group, an alkynyl-C₀₋₂alkyl group, up to two OR^(A2b) groups, a    C₀₋₂alkyl-N(R^(A2b))₂ group, a SC₁₋₄alkyl group, a S(O)₂C₁₋₄alkyl    group, a C(O)R^(A2b) group, a C(O)OR^(A2b) group, a C(O)N(R^(A2b))₂    group, or a —CN group;-   each R^(A2a) is, independently, hydrogen, C₁₋₄alkyl, a    C₅₋₆heteroaryl selected from imidazolyl, triazolyl, tetrazolyl,    pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, or    pyrazinyl, or two R^(A2a) and an intervening nitrogen atom form a    3-6 membered heterocyclic ring selected from aziridinyl, azetidinyl,    pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl,    tetrahydropyridinyl, piperazinyl, or morpholinyl;-   each R^(A2b) is, independently, hydrogen, C₁₋₄alkyl, or    C₃₋₄cycloalkyl;-   R^(A3) is hydrogen or C₁₋₂alkyl;-   each R^(A4) is, independently, deuterium, halogen, CN, C₁₋₄alkyl, or    OC₁₋₄alkyl, wherein each R^(A4) alkyl is optionally substituted with    up to 3 F atoms, two non-geminal OH groups, or one OC₁₋₂alkyl, or    two R^(A4) together with an intervening saturated carbon atom form a    spiral cyclopropyl or cyclobutyl ring;-   n is 0-3;-   Ring B is a ring system selected from

-   R^(B1) is hydrogen, C₁₋₄alkyl, (CH₂)₀₋₁C₃₋₆cycloalkyl,    C(O)C₁₋₂alkyl, (CH₂)₀₋₁-(4-6 membered)heterocyclyl ring wherein said    heterocyclic ring is selected from selected from oxetanyl,    tetrahydrofuranyl, tetrahydropyran, dioxanyl, dioxolanyl, or    pyrrolidinonyl, phenyl, benzyl, or (CH₂)₁₋₂(5-6 membered)heteroaryl    ring wherein said heteroaryl ring is selected from pyridinyl,    imidazolyl, or pyrazolyl, and wherein each of said R^(B1) alkyl,    cycloalkyl, phenyl, benzyl, heterocyclyl or heteroaryl groups is    optionally substituted with up to 3 F atoms, up to two C₁₋₂alkyl    groups, two non-geminal OH groups, or one OC₁₋₂alkyl;-   R^(B2) is hydrogen, C₁₋₄alkyl, OC₁₋₄alkyl;-   each R^(B3) is, independently, hydrogen, halogen, C₁₋₄alkyl,    C₂₋₄alkenyl, C₂₋₄alkynyl, CN, C(O)H, C(O)C₁₋₄alkyl, C(O)OC₁₋₄alkyl,    C(O)C₁₋₄alkyl, C(O)NH₂, C(O)NHC₁₋₄alkyl,    C(O)NH(CH₂)₀₋₁C₃₋₆cycloalkyl, C(O)NHCH₂oxetanyl,    C(O)NHCH₂tetrahydrofuranyl, C(O)NHCH₂tetrahydropyranyl,    C(O)NHphenyl, C(O)NHbenzyl, C(O)NHOH, C(O)NHOC₁₋₄alkyl,    C(O)NHO(CH₂)₀₋₁C₃₋₆cycloalkyl, C(O)NHO(CH₂)₀₋₁oxetanyl,    C(O)NHO(CH₂)₀₋₁tetrahydrofuranyl, C(O)NHO(CH₂)₀₋₁tetrahydropyranyl,    C(O)NHOphenyl, C(O)NHObenzyl, NH₂, NHC(O)C₁₋₄alkyl, OC₁₋₄alkyl,    SC₁₋₄alkyl, S(O)C₁₋₄alkyl, or a 5-membered-heteroaryl ring system    selected from furanyl, thiophenyl, imidazolyl, pyrrole, pyrazolyl,    and oxadiazolyl, wherein each R^(B3) group except hydrogen or    halogen is optionally substituted with Cl, up to three F atoms, up    to two non-geminal OH groups, up to two OC₁₋₂alkyl, one NH₂, one    NHC₁₋₂alkyl, one NHC(O)C₁₋₂alkyl, or one N(C₁₋₂alkyl)₂;-   each R^(B4) is, independently, hydrogen, halogen, C₁₋₄alkyl,    OC₁₋₄alkyl, SC₁₋₄alkyl, NH₂, NH(C₁₋₄alkyl), N(C₁₋₄alkyl)₂,    NHC(O)C₁₋₄alkyl, C(O)OH, C(O)OC₁₋₄alkyl, C(O)NH₂, C(O)NHC₁₋₄alkyl,    C(O)N(C₁₋₄alkyl)₂, CN, a morpholinyl ring, or an imidazolyl ring,    wherein each R^(B4) alkyl is optionally substituted with up to 3 F    atoms, two non-geminal OH groups, or one OC₁₋₂alkyl;-   R^(B5) is hydrogen, C₁₋₄alkyl, C(O)C₁₋₄alkyl, C(O)OC₁₋₄alkyl,    C(O)NH₂, C(O)NHC₁₋₄alkyl, or C(O)N(C₁₋₄alkyl)₂, wherein said R^(B5)    alkyl is optionally substituted with up to 3 F atoms, two    non-geminal OH groups, or one OC₁₋₂alkyl and-   R^(B6) is F or C₁₋₂alkyl, or two R^(B6) and an intervening carbon    atom from a spirocyclopropyl or spirocyclobutyl ring.

In one embodiment, the compound has the following formula:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In a further embodiment for any compound of formulae I-A-1 to I-A-3,I-A-6 to I-A-7, or I-A-9 to I-A-10, R^(A1) is C₁₋₄alkyl, OC₁₋₄alkyl, orN(R^(A1a))₂, wherein each R^(A1a) is, independently, hydrogen orC₁₋₄alkyl, or two R^(A1a) and an intervening nitrogen atom form a 3-6membered heterocyclic ring selected from aziridinyl, azetidinyl,pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl,tetrahydropyridinyl, piperazinyl, or morpholinyl, wherein each of saidR^(A1) alkyl or heterocyclyl groups is optionally substituted with up tothree F atoms, up to three ²H atoms, up to two C₁₋₂alkyl groups, aC₃₋₆cycloalkyl group, up to two C₀₋₂alkyl-OR^(A1b) groups, aC₀₋₂alkyl-N(R^(A1b))₂ group, a SC₁₋₄alkyl group, a C(O)R^(A1b) group, aC(O)OR^(A1b) group, a C(O)N(R^(A1b))₂ group, or a —CN group, whereineach R^(A1b) is, independently, hydrogen, C₁₋₂alkyl, or C₃₋₄cycloalkyl.

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae

In one embodiment, the compound has the following formula

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has the following formula:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In one embodiment, the compound has one of the following formulae:

In another embodiment, the B Ring of a compound of the invention islinked to the remainder of the molecule wherein

and R¹ is CH₃; except when Ring B is

wherein

and R¹ is CH₃.

In another embodiment, Q is CH for a compound of the invention.

In another embodiment, Ring A of compounds of the invention comprises aheterocyclyl or heteroaryl ring.

In a further embodiment, Ring A is selected from

In another further embodiment, Ring A is selected from

wherein R^(A2) is hydrogen, C₁₋₄alkyl, C₀₋₂alkyl-C₃₋₆cycloalkyl,C₀₋₂alkyl-(4-6 membered)heterocyclyl, C₂₋₄alkyl-OR^(A2a),C₀₋₂alkyl-C(O)N(R^(A2a))₂, C₀₋₂alkyl-S(O)₂—C₁₋₄alkyl, orC₀₋₂alkyl-C(O)OC₁₋₄alkyl, wherein each of said heterocyclyl is selectedfrom oxetan-2-yl, azetidin-2-yl, piperidin-4-yl, or1,1-dioxothietan-2-yl, and each of said R^(A2) groups is optionallysubstituted with up to three F atoms, up to two C₁₋₂alkyl groups, up totwo OR^(A2b) groups, a C₀₋₂alkyl-N(R^(A2b))₂ group, a C(O)R^(A2b) group,a C(O)OR^(A2b) group, a C(O)N(R^(A2b))₂ group, or a —CN group; eachR^(A2a) is, independently, H, C₁₋₄alkyl, or two R^(A2a) and anintervening nitrogen atom form a 3-6 membered heterocyclic ring selectedfrom aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl,piperidinonyl, tetrahydropyridinyl, piperazinyl, or morpholinyl; eachR^(A2b) is, independently, H or C₁₋₄alkyl; and n is 0.

In yet another further embodiment, Ring A is selected from

whereinR^(A2) is a hydrogen, C₁₋₄alkyl, C₀₋₂alkyl-C₃₋₆cycloalkyl,C₀₋₂alkyl-(4-6 membered)heterocyclyl, C₂₋₄alkyl-OR^(A2a),C₀₋₂alkyl-C(O)N(R^(A2a))₂, C₀₋₂alkyl-S(O)₂—C₁₋₄alkyl, orC₀₋₂alkyl-C(O)OC₁₋₄alkyl, wherein each of said heterocyclyl is selectedfrom oxetan-2-yl, azetidin-2-yl, piperidin-4-yl, or1,1-dioxothietan-2-yl, and each of said R^(A2) groups is optionallysubstituted with up to three F atoms, up to two C₁₋₂alkyl groups, up totwo OR^(A2b) groups, a C₀₋₂alkyl-N(R^(A2b))₂ group, a C(O)R^(A2b) group,a C(O)OR^(A2b) group, a C(O)N(R^(A2b))₂ group, or a —CN group; eachR^(A2a) is, independently, H, C₁₋₄alkyl, or two R^(A2a) and anintervening nitrogen atom form a 3-6 membered heterocyclic ring selectedfrom aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl,piperidinonyl, tetrahydropyridinyl, piperazinyl, or morpholinyl; eachR^(A2b) is, independently, H or C₁₋₄alkyl; and n is 0.

In yet another further embodiment, Ring A is selected from

whereinR^(A1) is C₁₋₄alkyl, C₀₋₄alkyl-C₃₋₆cycloalkyl, C₀₋₄alkyl-OR^(A1a),C₀₋₄alkyl-C₃₋₆cycloalkyl, C₀₋₄alkyl-N(R^(A1a))₂,N(R^(A1a))C₂₋₄alkyl-N(R^(A1a))₂, wherein each of said R^(A1) alkyl orcycloalkyl is optionally substituted with up to three F atoms, up tothree ²H atoms, or up to two C₀₋₂alkyl-OR^(A1b) groups; each R^(A1a) is,independently, hydrogen, C₁₋₄alkyl, a C(O)R^(A1b) group, or two R^(A1a)and an intervening nitrogen atom form a 3-6 membered heterocyclic ringselected from aziridinyl, azetidinyl, pyrrolidinyl, pyrrolidinonyl,piperidinyl, piperidinonyl, tetrahydropyridinyl, piperazinyl, ormorpholinyl, wherein each of said alkyl or heterocyclyl group of R^(A1a)is optionally substituted with up to three F atoms, up to two C₁₋₂alkylgroups, up to two OR^(A1b) groups, or a —CN group; each R^(A1b) is,independently, hydrogen or C₁₋₂alkyl; each R^(A4) is, independently,halogen, ²H, C₁₋₄alkyl, N(R^(1a))₂, or OC₁₋₄alkyl, wherein each R^(A4)alkyl is optionally substituted with up to 3 F atoms, up to twonon-geminal OH groups, or up to two OC₁₋₂alkyl, and wherein n is 0-3.

In yet another further embodiment, Ring A is selected from

whereineach R^(A4) is, independently, halogen, C₁₋₄alkyl, or OC₁₋₄alkyl,wherein each R^(A4) alkyl is optionally substituted with up to 3 Fatoms, up to two non-geminal OH groups, or up to two OC₁₋₂alkyl, andwherein n is 0-2.

In another embodiment, Ring B of compounds of the invention comprises aheterocyclyl or heteroaryl ring.

In one embodiment, Ring B is selected from

-   R^(B3) is C(O)NHC₁₋₄ alkyl, wherein said alkyl is optionally    substituted with up to three F atoms, two non-geminal OH groups, or    one OC₁₋₂alkyl; and-   each R^(B4) is, independently, hydrogen, ²H, F, C₁₋₄alkyl, or    OC₁₋₄alkyl, wherein each R^(B4) alkyl is optionally substituted with    up to 3 F atoms, two non-geminal OH groups, or one OC₁₋₂alkyl.

In a further embodiment, Ring A is

whereinR^(A1) is F, C₁₋₄alkyl, OC₁₋₄alkyl, OC₀₋₄alkyl-C₃₋₅cycloalkyl, NH₂,NHC₁₋₄alkyl, NHC₀₋₄alkyl-C₃₋₅cycloalkyl, or C₀₋₄alkyl-heterocyclyl,wherein said heterocyclic ring system is selected from oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, or morpholinyl, and each of saidalkyl, cycloalkyl, or heterocyclyl is optionally substituted with up tothree F atoms, up to three ²H atoms, up to two non-geminal OH groups, orup to two OC₁₋₂alkyl;each R^(A4) is, independently, F, ²H, OC₁₋₄alkyl, or NH₂; and n is 0-2.

In another embodiment, Ring B is

wherein

-   each of R^(B3) and R^(B4) is, independently, hydrogen, halogen, or    C₁₋₄alkyl, wherein each of said R^(B3) or R^(B4) alkyl is optionally    substituted with up to 3 F atoms, two non-geminal OH groups, or one    OC₁₋₂alkyl;-   R^(B5) is hydrogen, C₁₋₄alkyl, C(O)C₁₋₄alkyl, C(O)OC₁₋₄alkyl,    C(O)NH₂, C(O)NHC₁₋₄alkyl, or C(O)N(C₁₋₄alkyl)₂, wherein said R^(B5)    alkyl is optionally substituted with up to 3 F atoms, up to two    non-geminal OH groups, or up to two OC₁₋₂alkyl; and-   R^(B6) is F or C₁₋₂alkyl, or two R^(B6) and an intervening carbon    atom from a spirocyclopropyl or spirocyclobutyl ring.

In another aspect, the invention features a compound having formula

or a pharmaceutically acceptable salt thereof, wherein

-   X is N, CR^(A5);-   R^(A1) is F, C₁₋₄alkyl, C₃₋₅cycloalkyl, OC₁₋₄alkyl,    OC₁₋₄alkyl-C₃₋₅cycloalkyl, NH₂, NHC₁₋₄alkyl,    NHC₁₋₄alkyl-C₃₋₅cycloalkyl, or C₀₋₄alkyl-heterocyclyl, wherein said    heterocyclic ring system is selected from oxetanyl,    tetrahydrofuranyl, tetrahydropyran, or morpholinyl, and each of said    alkyl, cycloalkyl, or heterocyclyl is optionally substituted with up    to three F atoms, up to three ²H atoms, up to two non-geminal OH    groups, or up to two OC₁₋₂alkyl;-   each R^(A4) is, independently, H or ²H;-   R^(A5) is hydrogen, F, C₁₋₄alkyl, or OC₁₋₄alkyl, wherein each of    said alkyl is optionally substituted with up to three F atoms or up    to three ²H atoms;-   R^(B3) is C(O)NHC₁₋₄ alkyl, wherein said alkyl is optionally    substituted with up to three F atoms, up to three ²H atoms, up to    two non-geminal OH groups, or up to two OC₁₋₂alkyl; and-   each R^(B4) is, independently, hydrogen, deuterium, F, or C₁₋₄alkyl.

In another aspect, the invention features a compound having formula

wherein

-   X is N, CR^(A5);-   R^(A1) is F, C₁₋₄alkyl, C₃₋₅cycloalkyl, OC₁₋₄alkyl,    OC₁₋₄alkyl-C₃₋₅cycloalkyl, NH₂, NHC₁₋₄alkyl,    NHC₀₋₄alkyl-C₃₋₅cycloalkyl, or C₀₋₄alkyl-heterocyclyl, wherein said    heterocyclic ring system is selected from oxetanyl,    tetrahydrofuranyl, tetrahydropyran, or morpholinyl, and each of said    alkyl, cycloalkyl, or heterocyclyl is optionally substituted with up    to three F atoms, up to three ²H atoms, up to two non-geminal OH    groups, or up to two OC₁₋₂alkyl;-   each R^(A4) is, independently, H or ²H;-   R^(A5) is hydrogen, F, C₁₋₄alkyl, or OC₁₋₄alkyl, wherein each of    said alkyl is optionally substituted with up to three F atoms or up    to three ²H atoms;-   R^(B3) is C(O)NHC₁₋₄ alkyl, wherein said alkyl is optionally    substituted with up to three F atoms, up to three ²H atoms, up to    two non-geminal OH groups, or up to two OC₁₋₂alkyl; and-   each R^(B4) is, independently, hydrogen, deuterium, F, or C₁₋₄alkyl

In another aspect, the invention features a compound selected from thegroup of compounds listed in Table 1 or Table 2.

Compositions, Formulations, and Administration of Compounds of theInvention

In another embodiment, the invention provides a pharmaceuticalcomposition comprising a compound of any of the formulae describedherein and a pharmaceutically acceptable excipient. In a furtherembodiment, the invention provides a pharmaceutical compositioncomprising a compound of Table 1 or Table 2. In a further embodiment,the composition additionally comprises an additional therapeutic agent.

According to another embodiment, the invention provides a compositioncomprising a compound of this invention or a pharmaceutically acceptablederivative thereof and a pharmaceutically acceptable carrier, adjuvant,or vehicle. In one embodiment, the amount of compound in a compositionof this invention is such that is effective to measurably inhibit aDNA-PK in a biological sample or in a patient. In another embodiment,the amount of compound in the compositions of this invention is suchthat is effective to measurably inhibit DNA-PK. In one embodiment, thecomposition of this invention is formulated for administration to apatient in need of such composition. In a further embodiment, thecomposition of this invention is formulated for oral administration to apatient.

The term “patient,” as used herein, means an animal, preferably amammal, and most preferably a human.

It will also be appreciated that certain of the compounds of presentinvention can exist in free form for treatment, or where appropriate, asa pharmaceutically acceptable derivative thereof. According to thepresent invention, a pharmaceutically acceptable derivative includes,but is not limited to, pharmaceutically acceptable prodrugs, salts,esters, salts of such esters, or any other adduct or derivative whichupon administration to a patient in need is capable of providing,directly or indirectly, a compound as otherwise described herein, or ametabolite or residue thereof. As used herein, the term “inhibitoryactive metabolite or residue thereof” means that a metabolite or residuethereof is also an inhibitor of DNA-PK.

As used herein, the term “pharmaceutically acceptable salt” refers tothose salts which are, within the scope of sound medical judgment,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response and the like.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al., describe pharmaceutically acceptable saltsin detail in J. Pharmaceutical Sciences, 66:1-19, 1977, which isincorporated herein by reference. Pharmaceutically acceptable salts ofthe compounds of this invention include those derived from suitableinorganic and organic acids and bases. Examples of pharmaceuticallyacceptable, nontoxic acid addition salts are salts of an amino groupformed with inorganic acids such as hydrochloric acid, hydrobromic acid,phosphoric acid, sulfuric acid and perchloric acid or with organic acidssuch as acetic acid, oxalic acid, maleic acid, tartaric acid, citricacid, succinic acid or malonic acid or by using other methods used inthe art such as ion exchange. Other pharmaceutically acceptable saltsinclude adipate, alginate, ascorbate, aspartate, benzenesulfonate,benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate,citrate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate,gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide,2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, maleate, malonate, methanesulfonate,2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate,pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate,pivalate, propionate, stearate, succinate, sulfate, tartrate,thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and thelike. Salts derived from appropriate bases include alkali metal,alkaline earth metal, ammonium and N⁺(C₁₋₄ alkyl)₄ salts. This inventionalso envisions the quaternization of any basic nitrogen-containinggroups of the compounds disclosed herein. Water or oil-soluble ordispersable products may be obtained by such quaternization.Representative alkali or alkaline earth metal salts include sodium,lithium, potassium, calcium, magnesium, and the like. Furtherpharmaceutically acceptable salts include, when appropriate, nontoxicammonium, quaternary ammonium, and amine cations formed usingcounterions such as halide, hydroxide, carboxylate, sulfate, phosphate,nitrate, C₁₋₈ sulfonate and aryl sulfonate.

As described above, the pharmaceutically acceptable compositions of thepresent invention additionally comprise a pharmaceutically acceptablecarrier, adjuvant, or vehicle, which, as used herein, includes any andall solvents, diluents, or other liquid vehicle, dispersion orsuspension aids, surface active agents, isotonic agents, thickening oremulsifying agents, preservatives, solid binders, lubricants and thelike, as suited to the particular dosage form desired. In Remington: TheScience and Practice of Pharmacy, 21st edition, 2005, ed. D. B. Troy,Lippincott Williams & Wilkins, Philadelphia, and Encyclopedia ofPharmaceutical Technology, eds. J. Swarbrick and J. C. Boylan,1988-1999, Marcel Dekker, New York, the contents of each of which isincorporated by reference herein, are disclosed various carriers used informulating pharmaceutically acceptable compositions and knowntechniques for the preparation thereof. Except insofar as anyconventional carrier medium is incompatible with the compounds of theinvention, such as by producing any undesirable biological effect orotherwise interacting in a deleterious manner with any othercomponent(s) of the pharmaceutically acceptable composition, its use iscontemplated to be within the scope of this invention.

Some examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, ion exchangers,alumina, aluminum stearate, lecithin, serum proteins, such as humanserum albumin, buffer substances such as phosphates, glycine, sorbicacid, or potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulfate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, wool fat, sugars such aslactose, glucose and sucrose; starches such as corn starch and potatostarch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethyl cellulose and cellulose acetate; powdered tragacanth;malt; gelatin; talc; excipients such as cocoa butter and suppositorywaxes; oils such as peanut oil, cottonseed oil; safflower oil; sesameoil; olive oil; corn oil and soybean oil; glycols; such a propyleneglycol or polyethylene glycol; esters such as ethyl oleate and ethyllaurate; agar; buffering agents such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol, and phosphate buffer solutions, as well asother nontoxic compatible lubricants such as sodium lauryl sulfate andmagnesium stearate, as well as coloring agents, releasing agents,coating agents, sweetening, flavoring and perfuming agents,preservatives and antioxidants can also be present in the composition,according to the judgment of the formulator.

The compositions of the present invention may be administered orally,parenterally, by inhalation spray, topically, rectally, nasally,buccally, vaginally or via an implanted reservoir. The term “parenteral”as used herein includes subcutaneous, intravenous, intramuscular,intra-articular, intra-synovial, intrasternal, intrathecal, intraocular,intrahepatic, intralesional, epidural, intraspinal, and intracranialinjection or infusion techniques. Preferably, the compositions areadministered orally, intraperitoneally or intravenously. Sterileinjectable forms of the compositions of this invention may be aqueous oroleaginous suspension. These suspensions may be formulated according totechniques known in the art using suitable dispersing or wetting agentsand suspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a nontoxic parenterallyacceptable diluent or solvent, for example as a solution in1,3-butanediol. Among the acceptable vehicles and solvents that may beemployed are water, Ringer's solution and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium.

For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically-acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant, such as carboxymethyl cellulose or similar dispersingagents that are commonly used in the formulation of pharmaceuticallyacceptable dosage forms including emulsions and suspensions. Othercommonly used surfactants, such as Tweens, Spans and other emulsifyingagents or bioavailability enhancers which are commonly used in themanufacture of pharmaceutically acceptable solid, liquid, or otherdosage forms may also be used for the purposes of formulation.

The pharmaceutically acceptable compositions of this invention may beorally administered in any orally acceptable dosage form including, butnot limited to, capsules, tablets, aqueous suspensions or solutions. Inthe case of tablets for oral use, carriers commonly used include lactoseand corn starch. Lubricating agents, such as magnesium stearate, arealso typically added. For oral administration in a capsule form, usefuldiluents include lactose and dried cornstarch. When aqueous suspensionsare required for oral use, the active ingredient is combined withemulsifying and suspending agents. If desired, certain sweetening,flavoring or coloring agents may also be added.

Alternatively, the pharmaceutically acceptable compositions of thisinvention may be administered in the form of suppositories for rectaladministration. These can be prepared by mixing the agent with asuitable non-irritating excipient that is solid at room temperature butliquid at rectal temperature and therefore will melt in the rectum torelease the drug. Such materials include cocoa butter, beeswax andpolyethylene glycols.

The pharmaceutically acceptable compositions of this invention may alsobe administered topically, especially when the target of treatmentincludes areas or organs readily accessible by topical application,including diseases of the eye, the skin, or the lower intestinal tract.Suitable topical formulations are readily prepared for each of theseareas or organs.

Topical application for the lower intestinal tract can be effected in arectal suppository formulation (see above) or in a suitable enemaformulation. Topically-transdermal patches may also be used.

For topical applications, the pharmaceutically acceptable compositionsmay be formulated in a suitable ointment containing the active componentsuspended or dissolved in one or more carriers. Carriers for topicaladministration of the compounds of this invention include, but are notlimited to, mineral oil, liquid petrolatum, white petrolatum, propyleneglycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax andwater. Alternatively, the pharmaceutically acceptable compositions canbe formulated in a suitable lotion or cream containing the activecomponents suspended or dissolved in one or more pharmaceuticallyacceptable carriers. Suitable carriers include, but are not limited to,mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax,cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutically acceptable compositions may beformulated, e.g., as micronized suspensions in isotonic, pH adjustedsterile saline or other aqueous solution, or, preferably, as solutionsin isotonic, pH adjusted sterile saline or other aqueous solution,either with or without a preservative such as benzylalkonium chloride.Alternatively, for ophthalmic uses, the pharmaceutically acceptablecompositions may be formulated in an ointment such as petrolatum. Thepharmaceutically acceptable compositions of this invention may also beadministered by nasal aerosol or inhalation. Such compositions areprepared according to techniques well-known in the art of pharmaceuticalformulation and may be prepared as solutions in saline, employing benzylalcohol or other suitable preservatives, absorption promoters to enhancebioavailability, fluorocarbons, and/or other conventional solubilizingor dispersing agents.

Most preferably, the pharmaceutically acceptable compositions of thisinvention are formulated for oral administration.

Liquid dosage forms for oral administration include, but are not limitedto, pharmaceutically acceptable emulsions, microemulsions, solutions,suspensions, syrups and elixirs. In addition to the active compounds,the liquid dosage forms may contain inert diluents commonly used in theart such as, for example, water or other solvents, solubilizing agentsand emulsifiers such as ethyl alcohol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1,3-butylene glycol, dimethylformamide, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor, and sesame oils),glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fattyacid esters of sorbitan, and mixtures thereof. Besides inert diluents,the oral compositions can also include adjuvants such as wetting agents,emulsifying and suspending agents, sweetening, flavoring, and perfumingagents.

Injectable preparations, for example, sterile injectable aqueous oroleaginous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectablesolution, suspension or emulsion in a nontoxic parenterally acceptablediluent or solvent, for example, as a solution in 1,3-butanediol. Amongthe acceptable vehicles and solvents that may be employed are water,Ringer's solution, U.S.P. and isotonic sodium chloride solution. Inaddition, sterile, fixed oils are conventionally employed as a solventor suspending medium. For this purpose any bland fixed oil can beemployed including synthetic mono- or diglycerides. In addition, fattyacids such as oleic acid are used in the preparation of injectables.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium prior to use.

In order to prolong the effect of a compound of the present invention,it is often desirable to slow the absorption of the compound fromsubcutaneous or intramuscular injection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material withpoor water solubility. The rate of absorption of the compound thendepends upon its rate of dissolution that, in turn, may depend uponcrystal size and crystalline form. Alternatively, dissolving orsuspending the compound in an oil vehicle accomplishes delayedabsorption of a parenterally administered compound form. Injectabledepot forms are made by forming microencapsule matrices of the compoundin biodegradable polymers such as polylactide-polyglycolide. Dependingupon the ratio of compound to polymer and the nature of the particularpolymer employed, the rate of compound release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the compound in liposomes or microemulsions that arecompatible with body tissues.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating excipients or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat ambient temperature but liquid at body temperature and therefore meltin the rectum or vaginal cavity and release the active compound.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and i) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case of capsules, tablets and pills, thedosage form may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such excipients as lactoseor milk sugar as well as high molecular weight polyethylene glycols andthe like. The solid dosage forms of tablets, dragees, capsules, pills,and granules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions that can be usedinclude polymeric substances and waxes. Solid compositions of a similartype may also be employed as fillers in soft and hard-filled gelatincapsules using such excipients as lactose or milk sugar as well as highmolecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form with one ormore excipients as noted above. The solid dosage forms of tablets,dragees, capsules, pills, and granules can be prepared with coatings andshells such as enteric coatings, release controlling coatings and othercoatings well known in the pharmaceutical formulating art. In such soliddosage forms the active compound may be admixed with at least one inertdiluent such as sucrose, lactose or starch. Such dosage forms may alsocomprise, as is normal practice, additional substances other than inertdiluents, e.g., tableting lubricants and other tableting aids such amagnesium stearate and microcrystalline cellulose. In the case ofcapsules, tablets and pills, the dosage forms may also comprisebuffering agents. They may optionally contain opacifying agents and canalso be of a composition that they release the active ingredient(s)only, or preferentially, in a certain part of the intestinal tract,optionally, in a delayed manner. Examples of embedding compositions thatcan be used include polymeric substances and waxes.

Dosage forms for topical or transdermal administration of a compound ofthis invention include ointments, pastes, creams, lotions, gels,powders, solutions, sprays, inhalants or patches. The active componentis admixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives or buffers as may be required.Ophthalmic formulation, eardrops, and eye drops are also contemplated asbeing within the scope of this invention. Additionally, the presentinvention contemplates the use of transdermal patches, which have theadded advantage of providing controlled delivery of a compound to thebody. Such dosage forms can be made by dissolving or dispensing thecompound in the proper medium. Absorption enhancers can also be used toincrease the flux of the compound across the skin. The rate can becontrolled by either providing a rate controlling membrane or bydispersing the compound in a polymer matrix or gel.

The compounds of the invention are preferably formulated in dosage unitform for ease of administration and uniformity of dosage. The expression“dosage unit form” as used herein refers to a physically discrete unitof agent appropriate for the patient to be treated. It will beunderstood, however, that the total daily usage of the compounds andcompositions of the present invention will be decided by the attendingphysician within the scope of sound medical judgment. The specificeffective dose level for any particular patient or organism will dependupon a variety of factors including the disorder being treated and theseverity of the disorder; the activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed, and like factors wellknown in the medical arts.

The amount of the compounds of the present invention that may becombined with the carrier materials to produce a composition in a singledosage form will vary depending upon the host treated, the particularmode of administration. Preferably, the compositions should beformulated so that a dosage of between 0.01-100 mg/kg body weight/day ofthe inhibitor can be administered to a patient receiving thesecompositions.

Depending upon the particular proliferative condition or cancer to betreated, additional therapeutic agents, which are normally administeredto treat or prevent that condition, may also be present in thecompositions of this invention. As used herein, additional therapeuticagents which are normally administered to treat or prevent a particularproliferative condition or cancer are known as “appropriate for thedisease, or condition, being treated.” Examples of additionaltherapeutic agents are provided infra.

The amount of additional therapeutic agent present in the compositionsof this invention will be no more than the amount that would normally beadministered in a composition comprising that therapeutic agent as theonly active agent. Preferably the amount of additional therapeutic agentin the presently disclosed compositions will range from about 50% to100% of the amount normally present in a composition comprising thatagent as the only therapeutically active agent.

Uses of the Compounds and Compositions of the Invention

In one embodiment, the invention provides a method of sensitizing a cellto an agent that induces a DNA lesion comprising the step of contactingthe cell with one or more DNA-PK inhibitors of formula I or subformulathereof (e.g., formulae I-A-1, I-A-2, . . . to I-A-51, I-B-1, I-B-2, . .. to I-B-42) or a DNA-PK inhibitor of formula II or formula III.

The invention further provides methods of potentiating a therapeuticregimen for treatment of cancer comprising the step of administering toan individual in need thereof an effective amount of a DNA-PK inhibitorof formula I, formula II, formula III, or subformulae thereof. In oneembodiment, the therapeutic regimen for treatment of cancer includesradiation therapy. Compounds of the invention are useful in instanceswhere radiation therapy is indicated to enhance the therapeutic benefitof such treatment. In addition, radiation therapy frequently isindicated as an adjuvant to surgery in the treatment of cancer. The goalof radiation therapy in the adjuvant setting is to reduce the risk ofrecurrence and enhance disease-free survival when the primary tumor hasbeen controlled. For example, adjuvant radiation therapy is indicated incancers, including but not limited to, breast cancer, colorectal cancer,gastric-esophageal cancer, fibrosarcoma, glioblastoma, hepatocellularcarcinoma, head and neck squamous cell carcinoma, melanoma, lung cancer,pancreatic cancer, and prostate cancer as described below.

The invention also can be practiced by including another anti-cancerchemotherapeutic agent with a compound of the invention in a therapeuticregimen for the treatment of cancer, with or without radiation therapy.The combination of a DNA-PK inhibitor compound of the invention withsuch other agents can potentiate the chemotherapeutic protocol. Forexample, the inhibitor compound of the invention can be administeredwith etoposide or bleomycin, agents known to cause DNA strand breakage.

The invention further relates to radiosensitizing tumor cells utilizinga compound of formula I, formula II, formula III, or subformulaethereof. The preferred compounds are those as described for thepharmaceutical compositions of the invention. A compound that can“radiosensitize” a cell, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amount to increase the sensitivity of cells toelectromagnetic radiation and/or to promote the treatment of diseasesthat are treatable with electromagnetic radiation (e.g., X-rays).Diseases that are treatable with electromagnetic radiation includeneoplastic diseases, benign and malignant tumors, and cancerous cells.

The present invention also provides methods of treating cancer in ananimal that includes administering to the animal an effective amount ofa DNA-PK inhibitor such as, for example, a compound of the invention.The invention further is directed to methods of inhibiting cancer cellgrowth, including processes of cellular proliferation, invasiveness, andmetastasis in biological systems. Methods include use of a compound ofthe invention as an inhibitor of cancer cell growth. Preferably, themethods are employed to inhibit or reduce cancer cell growth,invasiveness, metastasis, or tumor incidence in living animals, such asmammals. Methods of the invention also are readily adaptable for use inassay systems, e.g., assaying cancer cell growth and properties thereof,as well as identifying compounds that affect cancer cell growth.

Tumors or neoplasms include growths of tissue cells in which themultiplication of the cells is uncontrolled and progressive. Some suchgrowths are benign, but others are termed “malignant” and can lead todeath of the organism. Malignant neoplasms or “cancers” aredistinguished from benign growths in that, in addition to exhibitingaggressive cellular proliferation, they can invade surrounding tissuesand metastasize. Moreover, malignant neoplasms are characterized in thatthey show a greater loss of differentiation (greater“dedifferentiation”) and their organization relative to one another andtheir surrounding tissues. This property is also called “anaplasia.”

Neoplasms treatable by the present invention also include solid tumors,i.e., carcinomas and sarcomas. Carcinomas include those malignantneoplasms derived from epithelial cells which infiltrate (invade) thesurrounding tissues and give rise to metastases. Adenocarcinomas arecarcinomas derived from glandular tissue, or from tissues which formrecognizable glandular structures. Another broad category of cancersincludes sarcomas, which are tumors whose cells are embedded in afibrillar or homogeneous substance like embryonic connective tissue. Theinvention also enables treatment of cancers of the myeloid or lymphoidsystems, including leukemias, lymphomas, and other cancers thattypically do not present as a tumor mass, but are distributed in thevascular or lymphoreticular systems.

DNA-PK activity can be associated with various forms of cancer in, forexample, adult and pediatric oncology, growth of solidtumors/malignancies, myxoid and round cell carcinoma, locally advancedtumors, metastatic cancer, human soft tissue sarcomas, including Ewing'ssarcoma, cancer metastases, including lymphatic metastases, squamouscell carcinoma, particularly of the head and neck, esophageal squamouscell carcinoma, oral carcinoma, blood cell malignancies, includingmultiple myeloma, leukemias, including acute lymphocytic leukemia, acutenonlymphocytic leukemia, chronic lymphocytic leukemia, chronicmyelocytic leukemia, and hairy cell leukemia, effusion lymphomas (bodycavity based lymphomas), thymic lymphoma lung cancer, including smallcell carcinoma, cutaneous T cell lymphoma, Hodgkin's lymphoma,non-Hodgkin's lymphoma, cancer of the adrenal cortex, ACTH-producingtumors, nonsmall cell cancers, breast cancer, including small cellcarcinoma and ductal carcinoma, gastrointestinal cancers, includingstomach cancer, colon cancer, colorectal cancer, polyps associated withcolorectal neoplasia, pancreatic cancer, liver cancer, urologicalcancers, including bladder cancer, including primary superficial bladdertumors, invasive transitional cell carcinoma of the bladder, andmuscle-invasive bladder cancer, prostate cancer, malignancies of thefemale genital tract, including ovarian carcinoma, primary peritonealepithelial neoplasms, cervical carcinoma, uterine endometrial cancers,vaginal cancer, cancer of the vulva, uterine cancer and solid tumors inthe ovarian follicle, malignancies of the male genital tract, includingtesticular cancer and penile cancer, kidney cancer, including renal cellcarcinoma, brain cancer, including intrinsic brain tumors,neuroblastoma, astrocytic brain tumors, gliomas, metastatic tumor cellinvasion in the central nervous system, bone cancers, including osteomasand osteosarcomas, skin cancers, including malignant melanoma, tumorprogression of human skin keratinocytes, squamous cell cancer, thyroidcancer, retinoblastoma, neuroblastoma, peritoneal effusion, malignantpleural effusion, mesothelioma, Wilms's tumors, gall bladder cancer,trophoblastic neoplasms, hemangiopericytoma, and Kaposi's sarcoma.Methods to potentiate treatment of these and other forms of cancer areembraced by the invention.

The invention provides a method of inhibiting DNA-PK activity in abiological sample that includes contacting the biological sample with acompound or composition of the invention. The term “biological sample,”as used herein, means a sample outside a living organism and includes,without limitation, cell cultures or extracts thereof; biopsied materialobtained from a mammal or extracts thereof; and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.Inhibition of kinase activity, particularly DNA-PK activity, in abiological sample is useful for a variety of purposes known to one ofskill in the art. An example includes, but is not limited to, theinhibition of DNA-PK in a biological assay. In one embodiment, themethod of inhibiting DNA-PK activity in a biological sample is limitedto non-therapeutic methods.

Preparation of Compounds of the Invention

As used herein, all abbreviations, symbols and conventions areconsistent with those used in the contemporary scientific literature.See, e.g., Janet S. Dodd, ed., The ACS Style Guide: A Manual for Authorsand Editors, 2nd Ed., Washington, D.C.: American Chemical Society, 1997.The following definitions describe terms and abbreviations used herein:

-   BPin pinacol boronate ester-   Brine a saturated NaCl solution in water-   DCM dichloromethane-   DIEA diisopropylethylamine-   DMA dimethylacetamide-   DME dimethoxyethane-   DMF dimethylformamide-   DMSO methylsulfoxide-   DTT dithiothreitol-   EtDuPhos    (2R,5R)-1-[2-[(2R,5R)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane-   ESMS electrospray mass spectrometry-   Et₂O ethyl ether-   EtOAc ethyl acetate-   EtOH ethyl alcohol-   HATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HEPES 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid-   HPLC high performance liquid chromatography-   IPA isopropanol-   LAH lithium aluminum hydride-   LC-MS liquid chromatography-mass spectrometry-   LDA lithium diisoproylethylamide-   Me methyl-   MeOH methanol-   MTBE methyl t-butyl ether-   NMP N-methylpyrrolidine-   Pd(dppf)Cl₂ 1,1′ bis(diphenylphosphino)-ferrocene dichloro-palladium-   Ph phenyl-   RT or rt room temperature-   SFC supercritical fluid chromatography-   SPhos 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl-   TBAI tetrabutylammonium iodide-   TBME tert-butylmethyl ether-   tBu tertiary butyl-   THF tetrahydrofuran-   TEA triethylamine-   TMEDA tetramethylethylenediamine-   VPhos    [3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium

General Synthetic Procedures

In general, the compounds of this invention may be prepared by methodsdescribed herein or by other methods known to those skilled in the art.

Example 1. General Preparation of the Compounds of Formula I

Compounds of formula I can be prepared as outlined below in Scheme1—Method A. Accordingly, as shown in step 1-i of Scheme 1,4,6-dichloropyrimidine is reacted with an amine of formula A in thepresence of a tertiary amine base at elevated temperatures to produce acompound of formula B. As shown in step 1-ii of Scheme 1, reaction of acompound of formula B with a suitable boronic acid or boronate offormula C in the presence of an appropriate palladium catalyst producescompounds of formula I. Procedures for preparing a boronate or boronicacid from aryl or heteroaryl halides are described in Boronic Acids,ISBN: 3-527-30991-8, Wiley-VCH, 2005 (Dennis G. Hall, editor). In oneexample, the halogen is bromine and the boronate is prepared by reactingthe aryl or heteroaryl bromide with4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane.In subsequent coupling reactions, boronates or boronic acids so formedcan be reacted with halopyrimidines in the presence of a palladiumcatalyst such as 1,1′ bis(diphenylphosphino)-ferrocenedichloro-palladium⋅dichloromethane [Pd(dppf)Cl₂].

Alternatively, as shown in Scheme 1—Method B, the order of couplingcompounds of formula A and compounds of formula C to4,6-dichloropyrimidine can be reversed to produce the formula Icompounds of the invention.

Compounds of formula I can also be prepared by employing Suzukiboronate-type couplings to form the carbon-carbon bond between a carbonatom of aromatic or heteroaromatic B Ring moieties and the unsaturation2-carbon of N-allylpyrimidin-4-amines. In one example, as shown inScheme 1—Method C, compounds of formula D are reacted with allylamineboronates of formula E to produce compounds of formula F. Subsequentreaction of the boronate with an aromatic or heteroaromatic B Ringhalide of formula G results in compounds of formula H, the double bondof which can be reduced to form compounds of formula I.

Alternatively, as shown in Scheme 1—Method D, the carbon-carbon bondbetween aromatic or heteroaromatic B Ring and the remainder of themolecule in compounds of formula I is formed by reacting vinyl halidesof formula K and B-ring boronates of formula L. As before, the doublebond of resulting compound of formula H can be reduced to form compoundsof formula I.

As previously mentioned, boronate or boronic acid intermediates can beprepared by reacting an aryl or heteroaryl, or vinyl halide with4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolanein the presence of a palladium catalyst such as 1,1′bis(diphenylphosphino)-ferrocene dichloro-palladium⋅dichloromethane[Pd(dppf)Cl₂]. For example, in order to prepare Ring A boronateintermediates of Formula O, the procedures outlined in Example 2 can befollowed.

Example 2. General Preparation of the Ring A Intermediates of Formula O

As shown in step 2-i of Scheme 2, to a solution of a compound of formulaM (1 equiv.) and K₂CO₃ (3 equiv.) in DMF (0.3 M) was added an alkylbromide (2 equiv.) at room temperature. The reaction mixture was thenstirred at 80° C. for 5 hours. The reaction was cooled down to roomtemperature and filtered over a pad of diatomaceous earth. The resultingcake was washed with EtOAc. To the filtrate was added H₂O and the twophases were separated. The aqueous phase was extracted with EtOAc andthe organic phase was washed with brine. The combined organic phaseswere dried over Na₂SO₄ and evaporated. The residue was purified bymedium pressure silica gel chromatography (0→100% EtOAc in hexanes) toprovide intermediate N.

As shown in step 2-ii of Scheme 2, A solution of the5-bromo-pyrazolo[3,4-b]pyridine of formula N (1 equiv.), bis-pinacolborane (1.15 equiv.), KOAc (3 equiv.) in 2-methyl-THF (0.3 M) wasdegassed with a stream of N₂ for 20 min. Then, Pd(dppf)Cl₂ (0.05 equiv.)was added to the reaction mixture. The resulting solution was heated ina sealed tube at 120° C. for 3 h in an oil bath. The solution was cooleddown to room temperature and filtered over a pad of Florisil®. Thefiltrate was evaporated and the resulting compound of formula O wasproduced. In many cases, these compounds could be subsequently usedwithout any further purification.

The procedure of Example 2 can be followed to prepare the followingcompounds.

2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)ethanol:ESMS (M+H)=289.43; ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=0.7 Hz, 1H),8.48 (d, J=0.4 Hz, 1H), 7.97 (s, 1H), 4.63 (t, J=4.6 Hz, 2H), 4.45 (s,1H), 4.05 (t, J=4.6 Hz, 2H) and 1.30 (s, 12H)

1-(2-methoxyethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine:ESMS (M+H)=303.16; ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=1.2 Hz, 1H),8.44 (d, J=1.2 Hz, 1H), 7.97 (s, 1H), 4.67 (t, J=5.6 Hz, 2H), 3.82 (t,J=5.6 Hz, 2H), 3.25 (s, 3H) and 1.30 (s, 12H)

1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine:ESMS (M+H)=301.14; ¹H NMR (400 MHz, CDCl₃) δ 8.79 (d, J=1.0 Hz, 1H),8.44 (d, J=1.0 Hz, 1H), 7.96 (s, 1H), 4.35 (d, J=7.1 Hz, 2H), 1.35 (s,12H) and 0.49-0.39 (m, 5H)

1-(thietane-1,1-dioxide)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine:ESMS (M+H)=350.37

N-ethyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)ethanamide:ESMS (M+H)=331.66

1-(2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)ethyl)pyrrolidin-2-one:ESMS (M+H)=358.12

1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine:ESMS (M+H)=302.16; ¹H NMR (400 MHz, CDCl₃) δ 8.80 (d, J=10.8 Hz, 1H),8.45 (s, 1H), 8.06 (s, 1H), 6.19 (p, J=7.2 Hz, 1H), 5.25 (t, J=6.5 Hz,2H), 5.08-5.03 (m, 2H), 1.30 (s, 12H)

1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridine:ESMS (boronic acid, M+H)=178.23; ¹H NMR (400 MHz, CDCl₃) δ d 8.93 (d,J=1.2 Hz, 1H), 8.45 (d, J=1.1 Hz, 1H), 7.87 (s, 1H), 4.18 (s, 3H) and1.29 (s, 12H)

ethyl2-methyl-2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)propanoate:ESMS (M+H)=360.29; ¹H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 8.47 (s, 1H),8.04 (s, 1H), 4.16-4.05 (m, 2H), 1.95 (s, 6H), 1.30 (s, 12H), 1.13-1.05(m, 3H)

methyl2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazolo[3,4-b]pyridin-1-yl)ethanoate:ESMS (M+H)=317.2; ¹H NMR (400 MHz, CDCl₃) δ 8.90 (d, J=1.1 Hz, 1H), 8.56(t, J=3.9 Hz, 1H), 8.11 (d, J=7.7 Hz, 1H), 5.36 (s, 2H), 3.76 (s, 3H),1.38 (s, 12H)

1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine:ESMS (M+H)=301.4; ¹H NMR (400 MHz, CDCl3) δ 8.72-8.52 (m, 1H), 8.41-8.28(m, 1H), 7.71 (d, J=3.4 Hz, 1H), 6.64 (dd, J=24.9, 3.5 Hz, 1H), 6.18(dd, J=13.6, 6.6 Hz, 1H), 5.30-5.02 (m, 4H), 1.28 (s, 12H)

2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridin-1-yl)ethanol:ESMS (M+H)=289.32

1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine:ESMS (M+H)=299.38

1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine:ESMS (M+H)=260.14; ¹H NMR (400 MHz, CDCl₃) δ 8.63 (d, J=1.0 Hz, 1H),8.28 (d, J=1.0 Hz, 1H), 7.08 (d, J=3.4 Hz, 1H), 6.38 (d, J=3.4 Hz, 1H),3.83 (s, 3H) and 1.30 (s, 12H)

2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethanol:ESMS (M+H)=289.33

1-(cyclopropylmethyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole:ESMS (M+H)=298.02

2-(3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethanol:ESMS (M+H)=302.22; ¹H NMR (400 MHz, CDCl₃) δ 8.18-8.04 (m, 1H), 7.70(dd, J=18.8, 8.1 Hz, 1H), 7.30 (dd, J=20.1, 8.5 Hz, 1H), 4.36 (dt,J=9.4, 5.1 Hz, 2H), 4.22-3.96 (m, 2H), 2.58-2.47 (m, 3H), 1.20 (t, J=2.0Hz, 12H)

2-(4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-1-yl)ethanol:ESMS (M+H)=302.22; ¹H NMR (400 MHz, CDCl₃) δ 8.07-7.93 (m, 1H), 7.71 (t,J=9.9 Hz, 1H), 7.15 (d, J=8.6 Hz, 1H), 4.50-4.34 (m, 2H), 4.16-3.98 (m,2H), 2.80-2.67 (m, 3H), 1.20 (s, 12H)

1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole:ESMS (M+H)=301.34

3-methyl-1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole:ESMS (M+H)=315.57; ¹H NMR (400 MHz, CDCl₃) δ 8.23 (d, J=8.2 Hz, 1H),7.82 (d, J=8.5 Hz, 1H), 7.49-7.41 (m, 1H), 5.74 (p, J=7.1 Hz, 1H), 5.31(t, J=6.5 Hz, 2H), 5.12 (t, J=7.2 Hz, 2H), 2.63 (d, J=5.1 Hz, 3H), 1.40(s, 12H)

4-methyl-1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole:ESMS (M+H)=315.57; ¹H NMR (400 MHz, CDCl₃) δ 8.06 (d, J=21.0 Hz, 1H),7.72 (d, J=8.5 Hz, 1H), 7.32-7.20 (m, 1H), 5.76-5.63 (m, 1H), 5.24 (dd,J=12.3, 5.7 Hz, 2H), 5.05 (t, J=7.3 Hz, 2H), 2.76 (s, 3H), 1.30 (s, 12H)

6-methyl-1-(oxetan-3-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole:ESMS (M+H)=315.57; ¹H NMR (400 MHz, CDCl₃) δ 8.17 (s, 1H), 7.94 (s, 1H),7.19 (s, 1H), 5.76-5.59 (m, 1H), 5.29-5.18 (m, 2H), 5.12-4.99 (m, 2H),2.61 (s, 3H), 1.29 (s, 12H)

Example 3. Preparation ofN-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine(Compound 68)

As shown in step 3-i of Scheme 3, to a solution of 2-bromophenol (15 g,86.7 mmol) in DMF (180 mL) at 0° C. was added3-bromo-2-methyl-prop-1-ene (12.8 g, 9.61 mL, 95.37 mmol) followed byK₂CO₃ (23.96 g, 173.4 mmol) and TBAI (384 mg, 1.04 mmol). The reactionmixture was then stirred at RT for 24 hours and quenched with H₂O (90mL). The aqueous phase was extracted with EtOAc and the organic phasewas dried over Na₂SO₄. Removal of the volatiles under reduced pressuregave 1-bromo-2-((2-methylallyl)oxy)benzene (Compound 2001, 19.12 g, 97%yield, colorless liquid): 1H NMR (400 MHz, CDCl₃) δ 7.46 (dd, J=1.5, 7.8Hz, 1H), 7.18-7.13 (m, 1H), 6.81-6.73 (m, 2H), 5.09 (s, 1H), 4.93 (t,J=1.1 Hz, 1H), 4.42 (s, 2H) and 1.78 (s, 3H) ppm. This material was usedas is in subsequent reactions.

As shown in step 3-ii of Scheme 3, a solution of Compound 2001 (13.8 g,60.7 mmol), NaOAc (12.46 g, 151.9 mmol), tetraethylammonium chloridehydrate (13.4 g, 72.9 mmol), and sodium formate (4.95 g, 72.9 mmol) inDMF (140 mL) was degassed for 30 min using a N₂ stream. Pd(OAc)₂ (682.1mg, 3.04 mmol) was added and the mixture was heated to 90° C. for 4hours. The reaction mixture was cooled down to RT and diluted with Et₂O(50 mL). The resulting solution was filtered though diatomaceous earthand the filtrate was washed with H₂O and brine. The organic phase wasdried over Na₂SO₄, concentrated under reduced pressure, and purified bymedium pressure chromatography on silica gel (0 to 20% EtOAc in hexanes)to give 3,3-dimethyl-2,3-dihydrobenzofuran (Compound 2002, 3.86 g, 43%yield) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 7.03 (d, J=7.6 Hz,2H), 6.81 (t, J=7.4 Hz, 1H), 6.72 (d, J=7.8 Hz, 1H), 4.15 (d, J=0.7 Hz,2H) and 1.27 (s, 6H) ppm.

As shown in step 3-iii of Scheme 3, to a solution of TMEDA (3.93 g, 5.11mL, 33.8 mmol) in Et₂O (60 mL) was added sec-butyllithium (22.3 mL of1.4 M, 31.2 mmol) at −78° C. After 10 minutes at −78° C.,3,3-dimethyl-2H-benzofuran (Compound 2002, 3.86 g, 26.0 mmol) in Et₂O(60 mL) was added dropwise over 15 min. After 10 min, the mixture wasstirred at 0° C. for 30 min. Then, the solution was cooled to −78° C.and DMF (4.76 g, 5.04 mL, 65.1 mmol) was added dropwise. The reactionmixture was stirred at −78° C. for 10 minutes and was then warmed to 0°C. over 2 hours. The reaction was quenched with IN HCl (20 mL) anddiluted with hexane/Et₂O (1:1, 50 mL). The organics were dried overNa₂SO₄ and the volatiles were removed under reduced pressure to give3,3-dimethyl-2,3-dihydrobenzofuran-7-carbaldehyde (Compound 2003, 4.1 g,89% yield): ¹H NMR (400 MHz, CDCl₃) δ 10.14 (s, 1H), 7.53 (dd, J=1.3,7.8 Hz, 1H), 7.25 (dd, J=1.3, 7.2 Hz, 1H), 6.90 (t, J=7.5 Hz, 1H), 4.34(s, 2H) and 1.30 (s, 6H) ppm; ESMS (M+H)=177.25.

As shown in step 3-iv of Scheme 3, to a solution of3,3-dimethyl-2H-benzofuran-7-carbaldehyde (0.5 g, 2.837 mmol) in AcOH(11.1 mL) was added nitromethane (519.5 mg, 461.0 μL, 8.511 mmol) andammonium acetate (546.7 mg, 7.092 mmol) at RT. The reaction mixture wasthen heated at 110° C. for 2 hours. The reaction mixture was then cooledand the volatiles removed under reduced pressure. The residue wasdissolved in DCM, the organic phase was washed with H₂O and brine, driedover Na₂SO₄, concentrated under reduced pressure, and purified by mediumpressure chromatography on silica gel (0 to 75% EtOAc in hexanes) togive (E)-3,3-dimethyl-7-(2-nitrovinyl)-2,3-dihydrobenzofuran (Compound2004, 160 mg, 34% yield) as a yellow solid: ¹H NMR (400 MHz, CDCl₃) δ7.91 (q, J=13.4 Hz, 2H), 7.14 (t, J=7.1 Hz, 2H), 6.88 (t, J=7.5 Hz, 1H),4.34 (s, 2H) and 1.30 (s, 6H) ppm; ESMS (M+H)=220.02.

As shown in step 3-v of Scheme 3, to a solution of LiAlH₄ (4.01 mL of1M/THF, 4.01 mmol) was added(E)-3,3-dimethyl-7-(2-nitrovinyl)-2,3-dihydrobenzofuran (160 mg, 0.72mmol) in THF (14.0 mL) at RT. The yellow solution was stirred at RT for15 hours. The reaction was quenched very slowly with water (15 mL) andextracted with Et₂O and EtOAc. The organics were dried over Na₂SO₄ andconcentrated under reduced pressure to give2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethanamine (Compound 2005,139 mg, 99% yield): ¹H NMR (400 MHz, CDCl₃) δ 6.90 (dd, J=6.2, 6.9 Hz,2H), 6.79-6.71 (m, 1H), 4.15 (s, 2H), 2.88 (t, J=6.9 Hz, 2H), 2.65 (t,J=6.9 Hz, 2H) and 1.26 (s, 6H) ppm; ESMS (M+H)=192.07.

As shown in step 3-vi of Scheme 3, a solution of 4,6-dichloropyrimidine(111.6 mg, 0.726 mmol), 2-(3,3-dimethyl-2H-benzofuran-7-yl)ethanamine(139 mg, 0.726 mmol), Na₂CO₃ (231.1 mg, 2.180 mmol) in i-PrOH (5.56 mL)was sealed in a microwave-type tube and heated at 90° C. in an oil bathfor 18 hours. The reaction mixture was filtered through a pad ofdiatomaceous earth, the volatiles removed under reduced pressure, andthe residue purified by medium pressure chromatography on silica gel (0to 100% EtOAc in hexanes) to give6-chloro-N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amine(Compound 2006) as a colorless oil: ¹H NMR (400 MHz, CDCl₃) δ 8.24 (s,1H), 6.94 (d, J=7.3 Hz, 1H), 6.88 (d, J=7.4 Hz, 1H), 6.78 (t, J=7.4 Hz,1H), 6.25 (s, 1H), 4.20 (d, J=5.9 Hz, 2H), 4.05 (d, J=7.1 Hz, H), 3.47(s, 2H), 2.83 (t, J=6.6 Hz, 2H), 1.50 (s, 2H) and 1.27 (s, 6H) ppm; ESMS(M+H)=304.06.

As shown in step 3-vii of Scheme 3, a solution of-chloro-N-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)pyrimidin-4-amine(60 mg, 0.197 mmol),1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine(71.86 mg, 0.237 mmol), Na₂CO₃ (296.2 μL of 2M, 0.592 mmol), and[3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium(VPhos, 8.1 mg, 0.0158 mmol) in i-PrOH (1.6 mL) was degassed using astream of N₂ for 30 minutes. Pd(OAc)₂ (0.88 mg, 0.0039 mmol) was addedand the solution was heated to 90° C. for 2 hours. The solution wasconcentrated under reduced pressure and purified by medium pressurechromatography on silica gel (0 to 100% (10% MeOH/EtOAc) in hexanes) togiveN-(2-(3,3-dimethyl-2,3-dihydrobenzofuran-7-yl)ethyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine(Compound 68, 32.4 mg, 36%) as a white solid: ¹H NMR (400 MHz, CDCl₃) δ8.69 (s, 1H), 8.49 (s, 1H), 8.07 (d, J=8.1 Hz, 1H), 6.94-6.90 (m, 2H),6.77 (t, J=7.3 Hz, 1H), 6.62 (d, J=8.9 Hz, 1H), 6.55 (s, 1H), 5.30 (s,1H), 4.20 (s, 2H), 3.60 (s, 6H), 2.86 (t, J=6.4 Hz, 2H), 2.45 (s, 4H),2.28 (s, 3H) and 1.27 (s, 6H) ppm; ESMS (M+H)=445.09.

Example 4. Preparation(S)—N-(2-(2-Methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine(Compound 32)

As shown in step 4-i of Scheme 4, to a solution of diisopropylamine(6.70 g, 9.28 mL, 66.2 mmol) in THF (60 mL) at −78° C. under N₂ wasadded n-butyllithium (33.1 mL of 2.0 M in cyclohexane, 66.2 mmol) andthe solution was stirred for 40 minutes. A solution of2-(2-methoxyphenyl)acetic acid (5.00 g, 30.1 mmol) in THF (30 mL) wasadded dropwise, then the reaction was allowed to warm to roomtemperature over one hour. The reaction was then cooled to −78° C. andiodomethane (4.27 g, 1.87 mL, 30.1 mmol) was added to the reaction inone portion. The reaction was warmed to room temperature 18 hours, 15 mLof water was added, and the organics were collected and the volatilesremoved under reduced pressure. The residue was acidified with IN HCland the crude product extracted with Et₂O (3×). The combined organicswere dried over MgSO₄, filtered, concentrated under reduced pressure,and the residue purified by medium pressure chromatography on silica gel(25 to 50% EtOAc in hexanes) to give 2-(2-methoxyphenyl)propanoic acidas a white solid (Compound 2008, 4.86 g, 85% yield): ¹H NMR (CDCl₃) δ7.31-7.21 (m, 2H), 7.01-6.84 (m, 2H), 4.09 (q, J=7.2 Hz, 1H), 3.84 (s,3H), 1.49 (d, J=7.2 Hz, 3H).

As shown in step 4-ii of Scheme 4, to a solution of2-(2-methoxyphenyl)propanoic acid (1.50 g, 7.91 mmol) in THF (20 mL) at0° C. was added lithium aluminum hydride (31.6 mL of 0.5 M solution,15.8 mmol) and the reaction was warmed to room temperature and stirredfor 3.5 hours. After the sequential addition of 0.7 mL water, 0.7 mL 1MNaOH, 1.9 mL water, and MgSO₄ to sequester the water, the reactionmixture was filtered through diatomaceous earth and concentrated underreduced pressure to give 2-(2-methoxyphenyl)-1-propanol as a clear,colorless liquid (Compound 2009, 1.41 g, 96% yield): ¹H NMR (CDCl₃) δ7.27-7.20 (m, 2H), 7.03-6.87 (m, 2H), 3.85 (s, 3H), 3.67 (m, 2H),3.54-3.42 (m, 1H), 1.54 (t, J=6.1 Hz, 1H), 1.29 (d, J=7.1 Hz, 3H).

As shown in step 4-iii of Scheme 4, a mixture of2-(2-methoxyphenyl)-1-propanol (1.31 g, 7.08 mmol), phthalimide (1.09 g,7.44 mmol), and PPh₃ resin (3.43 g, 10.6 mmol) was stirred at roomtemperature for 15 minutes to allow the resin to swell.Diisopropylazodicarboxylate (2.29 g, 2.24 mL, 10.6 mmol) was added andthe reaction was stirred for 18 hours. The reaction mixture was filteredthrough diatomaceous earth, which was subsequently washed with EtOAc andDCM. The filtrate was concentrated under reduced pressure and purifiedby medium pressure chromatography on silica gel (10 to 20% EtOAc inhexanes) to give 2-(2-(2-methoxyphenyl)propyl)isoindoline-1,3-dione as aclear, colorless oil (Compound 2010, 2.15 g, quantitative yield): ¹H NMR(CDCl₃) δ 7.81 (dd, J=5.5, 3.0 Hz, 2H), 7.69 (dd, J=5.5, 3.0 Hz, 2H),7.34-7.24 (m, 1H), 7.19 (ddd, J=8.1, 7.5, 1.7 Hz, 1H), 6.94 (td, J=7.5,1.1 Hz, 1H), 6.76 (dd, J=8.2, 0.9 Hz, 1H), 4.03-3.69 (m, 3H), 3.66 (s,3H), 1.32 (d, J=6.8 Hz, 3H).

As shown in step 4-iv of Scheme 4, to a stirred solution of2-(2-(2-methoxyphenyl)propyl)isoindoline-1,3-dione (363 mg, 1.23 mmol)in MeOH (4.0 mL) was added hydrazine (39.4 mg, 38.6 μL, 1.23 mmol) andthe reaction was stirred for 18 hours. The precipitate that had formedwas filtered, washed with MeOH, and the filtrate concentrated underreduced pressure to give 2-(methoxyphenyl)-1-propanamine as a lightyellow oil (Compound 2011, 144 mg, 71% yield): ¹H NMR (CDCl₃) δ7.27-7.13 (m, 2H), 6.95 (ddd, J=18.2, 12.3, 4.6 Hz, 2H), 3.84 (s, 3H),3.39-3.18 (m, 1H), 2.86 (qd, J=12.7, 6.8 Hz, 2H), 1.44 (s, 2H), 1.24 (d,J=7.0 Hz, 3H).

As shown in step 4-v of Scheme 4, a mixture of 4,6-dichloropyrimidine(817 mg, 5.49 mmol), 2-(2-methoxyphenyl)-1-propanamine (0.997 g, 6.03mmol), and DIEA (2.13 g, 2.87 mL, 16.5 mmol) in isopropanol (5.0 mL) wasstirred for 18 hours. The reaction mixture was concentrated underreduced pressure and the residue purified by medium pressurechromatography on silica gel (25% EtOAc in hexanes) to give6-chloro-N-(2-(2-methoxyphenyl)propyl)pyrimidin-4-amine as a colorlesssolid (Compound 2012, 1.18 g, 77% yield): ¹H NMR (CDCl₃) δ 8.31 (s, 1H),7.23 (dd, J=12.0, 4.5 Hz, 2H), 7.03-6.87 (m, 2H), 6.41 (s, 1H), 5.42 (s,1H), 3.89 (s, 3H), 3.67-3.18 (m, 3H), 1.35 (d, J=6.8 Hz, 3H).

As shown in step 4-vi of Scheme 4, a mixture of6-chloro-N-(2-(2-methoxyphenyl)propyl)pyrimidin-4-amine (75.0 mg, 0.270mmol),1-methyl-4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-pyridyl]piperazine(Compound 2007, 90.1 mg, 0.297 mmol), Pd(OAc)₂ (1.21 mg, 0.00540 mmol),[3-(2-dicyclohexylphosphanylphenyl)-2,4-dimethoxy-phenyl]sulfonyloxysodium(VPhos, 11.1 mg, 0.0216 mmol), and Na₂CO₃ (405 μL of 2 M, 0.810 mmol) inIPA (2 mL) was degassed and back-filled with N₂ (repeated 2×), thenheated to 90° C. for 4 hours. The reaction mixture was filtered throughdiatomaceous earth and concentrated under reduced pressure. The residuewas purified by medium pressure chromatography on silica gel (90-100%EtOAc in hexanes) to giveN-(2-(2-methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amineas a clear, yellow oil (Compound 2013, 48.0 mg, 42% yield): ¹H NMR(CDCl₃) δ 8.77 (d, J=2.2 Hz, 1H), 8.56 (s, 1H), 8.15 (dd, J=9.0, 2.5 Hz,1H), 7.28-7.21 (m, 2H), 7.01-6.89 (m, 2H), 6.72 (d, J=9.0 Hz, 1H), 6.60(s, 1H), 5.09 (bs, 1H), 3.87 (s, 3H), 3.76-3.65 (m, 4H), 3.65-3.46 (m,3H), 2.62-2.48 (m, 4H), 2.38 (s, 3H), 1.36 (d, J=6.7 Hz, 3H).

As shown in step 4-vii of Scheme 4,N-(2-(2-methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine(30.0 mg, 0.0710 mmol) was purified by supercritical fluidchromatography using a chiral OJ column and eluting with 40% MeOH (0.2%DEA) in CO₂ to give(S)—N-(2-(2-Methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amineas an off-white residue (Compound 32, 13.5 mg): ¹H NMR (CDCl₃) δ 8.77(d, J=2.3 Hz, 1H), 8.56 (s, 1H), 8.14 (dd, J=9.0, 2.5 Hz, 1H), 7.28-7.18(m, 2H), 7.04-6.86 (m, 2H), 6.71 (d, J=9.0 Hz, 1H), 6.59 (s, 1H), 5.24(d, J=47.4 Hz, 1H), 3.86 (s, 3H), 3.75-3.64 (m, 4H), 3.64-3.43 (m, 3H),2.65-2.47 (m, 4H), 2.37 (s, 3H), 1.36 (d, J=6.7 Hz, 3H).

Example 5. Preparation(S)—N-(2-(2-Methoxyphenyl)propyl)-6-(6-(4-methylpiperazin-1-yl)pyridin-3-yl)pyrimidin-4-amine(Compound 2016)

The chirality of asymmetric 1-carbon center of 2-aminoethyl-B-Ringmoieties can be ascertained by preparing intermediates analogous toCompound 2016 and using such intermediates in the preparation of thecompounds of the invention. Accordingly, the chirality of Compound 34was ascertained by preparing Compound 2009 as a mixture of racemateshaving an enantiomeric excess greatly in favor the (S)-configuration.See Evans D. A. et al., in J. Am. Chem. Soc., Vol 104, 1737-1739 (1982).Accordingly, as shown in step 5-i of Scheme 5, to a solution of2-(2-methoxyphenyl)acetic acid (5.00 g, 30.1 mmol) and Et₃N (6.70 g,9.23 mL, 66.2 mmol) in THF (150 mL) at −15° C. was added pivaloylchloride (3.70 g, 3.78 mL, 30.7 mmol) and the resulting solution wasstirred for 15 minutes. Lithium chloride (1.53 g, 36.1 mmol) and(4S)-4-benzyloxazolidin-2-one (6.29 g, 35.5 mmol) were added to thesolution and the reaction was warmed to room temperature over 18 hours.Saturated ammonium chloride was added and the reaction was extractedwith EtOAc (2×). The organic extracts were combined and washed withNaHCO₃ (sat), brine, dried over MgSO₄, filtered, and then concentratedunder reduced pressure. The residue was purified by medium pressuresilica gel chromatography (15 to 30% EtOAc in hexanes) to give(4S)-4-benzyl-3-[2-(2-methoxyphenyl)acetyl]-oxazolidin-2-one (Compound2014, 7.11 g, 72.6% yield) as a white solid: ¹H NMR (300 MHz, CDCl₃) δ7.42-7.15 (m, 7H), 6.96 (dd, J=15.6, 7.8 Hz, 2H), 4.79-4.65 (m, 1H),4.44-4.09 (m, 4H), 3.85 (s, 3H), 3.33 (dd, J=13.3, 2.9 Hz, 1H), 2.84(dd, J=13.3, 9.5 Hz, 1H).

As shown in step 5-ii of Scheme 5, to a solution of sodiumhexamethyldisilazide (NaHMDS, 5.06 g, 26.2 mmol) in THF (100 mL) underan atmosphere of nitrogen at −78° C. was added(4S)-4-benzyl-3-[2-(2-methoxyphenyl)acetyl]oxazolidin-2-one (7.11 g,21.9 mmol) and the reaction was stirred for 1.5 hours. Methyl iodide(3.08 g, 1.35 mL, 21.7 mmol) was then added dropwise and stirringcontinued at −78° C. for 4 hours, then the reaction was warmed to roomtemperature over 18 hours. The reaction was cooled to −20° C. andquenched with NH₄Cl (sat). The organics were removed under reducedpressure and the aqueous layer was extracted with DCM (3×). The organicextracts were combined and washed with brine, dried over MgSO₄,filtered, and concentrated under reduced pressure. The residue waspurified by medium pressure silica gel chromatography (5 to 25% EtOAc inhexanes) to give(4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)propanoyl]oxazolidin-2-one as awhite solid with a de of 9:1 (S/R). The solid was then purified viasupercritical fluid chromatography (SFC) on an IC column (10% MeOH/CO₂isocratic gradient) to give(4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)propanoyl]oxazolidin-2-one(Compound 2015, 3.14 g, 41.8% yield) with an enantiomeric excess of99.9% by analytical SFC: ¹H NMR (300 MHz, CDCl₃) δ 7.41-7.20 (m, 7H),6.96 (dd, J=13.8, 6.6 Hz, 1H), 6.93-6.84 (m, 1H), 5.30 (q, J=7.1 Hz,1H), 4.68 (qd, J=6.7, 3.5 Hz, 1H), 4.22-4.11 (m, 2H), 3.84 (s, 3H), 3.35(dd, J=13.3, 3.2 Hz, 1H), 2.82 (dd, J=13.3, 9.7 Hz, 1H), 1.64-1.46 (m,3H).

As shown in step 5-iii of Scheme 5, to an ice-cooled solution of(4S)-4-benzyl-3-[(2S)-2-(2-methoxyphenyl)-propanoyl]oxazolidin-2-one(3.10 g, 9.13 mmol) in THF (183 mL) and MeOH (1.24 mL) was added LiBH₄(9.13 mL of 2.0 M solution, 18.3 mmol) and the reaction was stirred at0° C. for 2 hours, then warmed to room temperature over 18 hours. Asolution of NaOH (18.6 mL of 2.0 M solution) was added and the reactionstirred until both layers were clear. The layers were separated and theaqueous layer was extracted with Et₂O (2×). The organic extracts werecombined and washed with H₂O, brine, dried over MgSO₄, filtered, andconcentrated. The residue was purified by flash chromatography on silicagel (0 to 20% EtOAc in hexanes) to give(2S)-2-(2-methoxyphenyl)propan-1-ol (Compound 2016, 1.49 g, 95.4% yield)as a clear, colorless liquid: ¹H NMR (300 MHz, CDCl3) δ 7.30-7.19 (m,2H), 6.98 (td, J=7.5, 1.0 Hz, 1H), 6.95-6.86 (m, 1H), 3.85 (s, 3H),3.83-3.63 (m, 2H), 3.56-3.38 (m, 1H), 1.84 (s, 1H), 1.30 (d, J=7.1 Hz,3H); [α]_(D) ^(25.7)+4.18 (c 1.11, CHCl₃). This optical rotationcompares with the rotation for Compound 2016 as described by Denmark S Eet al. in J. Am. Chem. Soc. Vol. 132, pages 3612-3620 (2010) and byMatsumoto T et al., in Bull. Chem. Soc. Jpn. Vol. 58, 340-345 (1985).

Compound 34 produced as described in Scheme 4 and resolved bypreparative SFC separation at the end of the synthesis was compared thesame compound prepared using the chiral intermediate Compound 1016 inorder to determine its absolute stereochemical configuration.

Example 6. Preparation(S)—N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)-6-(6-(methylamino)pyridin-3-yl)pyrimidin-4-amine(Compound 430)

As shown in step 6-i of Scheme 6, tert-butyl(2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl)carbamate(Compound 1017, 1.455 g, 5.138 mmol), 7-chlorofuro[3,2-b]pyridine (0.789g, 5.138 mmol), NaHCO₃ (8.56 mL of 1.2 M, 10.276 mmol), DMF (14.3 mL),and H₂O (4.8 mL) were combined. The resultant mixture was flushed withnitrogen gas for 10 minutes. Pd(dppf)Cl₂ (419.6 mg, 0.514 mmol) wasadded and the reaction was heated to 120° C. in the microwave for 30minutes. The crude reaction mixture was filtered over diatomaceous earthand the filter pad washed with ethyl acetate. The combined organics weredried (Na₂SO₄) and concentrated under reduced pressure. The residue waspurified by silica gel chromatography (0-20% EtOAc/hexanes) to furnishtert-butyl (2-(furo[3,2-b]pyridin-7-yl)allyl)carbamate (Compound 1019,0.94 g, 67% yield): LCMS=275.26 (M+H); ¹H NMR (400 MHz, CDCl₃) δ 8.51(d, J=5.0 Hz, 1H), 7.86 (d, J=2.2 Hz, 1H), 7.23 (d, J=4.8 Hz, 1H), 7.01(d, J=2.2 Hz, 1H), 6.02 (d, J=15.6 Hz, 1H), 5.69 (s, 1H), 4.79 (s, 1H),4.34 (d, J=5.6 Hz, 2H), 1.42 (s, 9H).

As shown in step 6-ii of Scheme 6, a mixture of tert-butyl(2-(furo[3,2-b]pyridin-7-yl)allyl)carbamate (0.940 g, 3.427 mmol), Pd/C(10%, 364.7 mg, 3.427 mmol), EtOAc (34.3 mL) and MeOH (34.3 mL) wasstirred under H₂ at 1 atm for 16 hours. The reaction mixture wasfiltered through diatomaceous earth and the filter pad was rinsed with1:1 EtOAc/MeOH. The combined filtrate was concentrated under reducedpressure. The crude residue was purified by silica gel chromatography(0-100% EtOAc/hexanes) to furnish tert-butyl(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)carbamate (Compound 1020,0.711 g, 75% yield): LCMS=279.47 (M+H); ¹H NMR (400 MHz, CDCl₃) δ 7.98(d, J=4.8 Hz, 1H), 6.86 (d, J=4.8 Hz, 1H), 4.64 (t, J=8.8 Hz, 2H), 4.54(s, 1H), 3.44-3.20 (m, 4H), 3.13-3.00 (m, 1H), 1.40 (s, 9H), 1.24 (d,J=6.9 Hz, 3H).

As shown in step 6-iii of Scheme 6, tert-butyl(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)carbamate (710 mg, 2.551mmol) was dissolved in HCl (19.13 mL of 4 M dioxane solution, 76.53mmol) and the reaction mixture stirred for 10 minutes. The solvent wasremoved under reduced pressure and the resulting2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propan-1-amine.2HCl (LCMS=179.22[M+H]) was used in the following reaction as is.

As shown in step 6-iv of Scheme 6, to a suspension of2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propan-1-amine.2HCl and4,6-dichloropyrimidine (456.0 mg, 3.061 mmol) in i-PrOH (17.01 mL) wasadded Et₃N (1.291 g, 1.778 mL, 12.76 mmol). The reaction mixture washeated at 80° C. for 2 h, cooled to room temperature, and partitionedbetween saturated aqueous NaHCO₃ and EtOAc. The aqueous layer wasfurther extracted with EtOAc (2×50 mL) and the combined organics werewashed with H₂O (50 mL) and brine (50 mL), dried (Na₂SO₄), filtered, andconcentrated under reduced pressure. The residue was purified by silicagel chromatography (0-100% EtOAc/hexanes, then isocratic EtOAc) toafford6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine(600.3 mg, 81% yield over two steps). Chiral SFC purification (20% MeOHat 5 mL/min on a ChiralPak® AD-H (4.6 mm×100 mm) column, 100 bar, 35°C., 220 nm) provided(S)-6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine(Compound 2021, 300 mg, SFC retention time 1.05 minutes): LCMS=291.04(M+H); ¹H NMR (400 MHz, CDCl₃) δ 8.32 (s, 1H), 8.00 (d, J=4.5 Hz, 1H),6.92 (d, J=4.4 Hz, 1H), 6.36 (s, 1H), 5.24 (s, 1H), 4.71 (t, J=8.9 Hz,2H), 3.61-3.35 (m, 4H), 3.23 (dd, J=14.0, 6.9 Hz, 1H), 1.35 (d, J=6.9Hz, 3H). The corresponding (R)-enantiomer had a retention time of 1.25minutes).

As shown in step 6-v of Scheme 6,(S)-6-chloro-N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)pyrimidin-4-amine(29.2 mg, 0.1003 mmol),N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine(30.7 mg, 0.2006 mmol), Na₂CO₃ (150.4 μL of 2 M aqueous solution, 0.3009mmol), and i-PrOH (2.0 mL) were combined and flushed with nitrogen gasfor 10 minutes. SPhos (water soluble, 10.28 mg, 0.0201 mmol) andPd(OAc)₂ (1.13 mg, 0.0050 mmol) were added and the reaction vesselsealed and heated to 120° C. in a microwave for 30 minutes. The reactionmixture was filtered over diatomaceous earth and the filtrate wasconcentrated under reduced pressure. The residue was purified byreversed-phase HPLC (0-30% CH₃CN/H₂O, 0.1% TFA). The TFA salt obtainedwas neutralized using a StratoSpheres™ PL-HCO₃ MP-Resin cartridge toprovide(S)—N-(2-(2,3-dihydrofuro[3,2-b]pyridin-7-yl)propyl)-6-(6-(methylamino)pyridin-3-yl)pyrimidin-4-amine(Compound 430, 23.8 mg, 65% yield): LCMS=364.12 (M+H); ¹H NMR (400 MHz,DMSO-d₆) δ 8.83 (s, 2H), 8.41 (s, 1H), 7.90 (d, J=5.1 Hz, 1H), 7.55 (s,1H), 7.39 (s, 1H), 7.01 (s, 1H), 6.77 (s, 1H), 4.61 (t, J=8.4 Hz, 2H),3.66-3.40 (m, 2H), 3.26-3.12 (m, 3H), 2.86 (d, J=4.5 Hz, 3H), 1.21 (d,J=6.6 Hz, 3H).

Example 7. Preparation of(S)—N⁶-(2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl)-N^(2′)-methyl-[4,5′-bipyrimidine]-2′,6-diamine(Compound 462)

As shown in step 7-i of Scheme 7,tert-Butyl-N-(2-bromoallyl)-N-tert-butoxycarbonyl carbamate (22.0 g,65.4 mmol),8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine(16.4 g, 62.3 mmol), and sodium carbonate (13.2 g, 125 mmol) werestirred in DME/H₂O (2:1, 246 mL) and the mixture flushed with nitrogengas for 30 minutes. After the addition of1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (1.53 g, 1.87 mmol) the mixture was flushed withnitrogen gas for another 5 minutes. The reaction mixture was heated at85° C. for 2 hours followed by the addition of MTBE (400 mL) and water(100 mL). The organics were washed with brine, dried over MgSO₄,filtered, concentrated under reduced pressure, diluted with a minimumamount of DCM, and purified by medium pressure silica gel chromatography(0-50% EtOAc/hexanes) to provide tert-butylN-tert-butoxycarbonyl-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)allyl]carbamate(Compound 2022, 19 g, 74% yield): ESMS=393.74 (M+H); ¹H NMR (300 MHz,CDCl₃) δ 7.75 (d, 1H), 6.75 (d, 1H), 5.30 (s, 1H), 5.25 (s, 1H), 4.55(s, 2H), 4.40 (m, 2H), 4.25 (m, 2H), 1.45 (s, 18H).

As shown in step 7-ii of Scheme 7, tert-butylN-tert-butoxycarbonyl-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)allyl]carbamate(18.9 g, 48.2 mmol) was stirred in EtOAc (200 mL) with 10%palladium/carbon (550 mg, 5.14 mmol). The reaction mixture was purged ofatmosphere which was replaced with hydrogen gas (3×) and stirred underan atmosphere of hydrogen for 5 hours. The atmosphere was replaced withnitrogen gas and the mixture filtered, concentrated to a minimum volumeunder reduced pressure, and purified by medium pressure silica gelchromatography (0-100% EtOAc/hexanes) to provide tert-butylN-tert-butoxycarbonyl-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]carbamate(Compound 2023, 18.06 g, 95% yield): ESMS=395.75 (M+H); ¹H NMR (300 MHz,CDCl₃) δ 7.75 (d, 1H), 6.75 (d, 1H), 4.45 (s, 2H), 4.25 (m, 2H),3.65-3.80 (m, 3H), 1.45 (s, 18H), 1.25 (3H).

As shown in step 7-iii of Scheme 7, tert-butylN-tert-butoxycarbonyl-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]carbamate(18.0 g, 45.6 mmol) was diluted with EtOH and aliquots were purified bysupercritical fluid chromatography on a Chiralpak® IC preparative column(10 mm×250 mm) eluting with 40% CO₂/EtOH at 35° C. and a pressure of 100atm. with a flow rate of 12 mL/min. The first peak to elute (retentiontime=6.61 min) was collected. All first peak fractions were combined andthe volatiles removed under reduced pressure to provide (S)-tert-butylN-tert-butoxycarbonyl-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]carbamate(Compound 2024, 7.74 g, 43% yield, enantiomeric excess=97.9%)

As shown in step 7-iv of Scheme 7, (S)-tert-butylN-tert-butoxycarbonyl-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]carbamate(7.74 g, 39.8 mmol) was dissolved in EtOH, HCl in IPA (60 mL of 4 Msolution, 240 mmol) was added and the reaction mixture was refluxed for1 hour. The reaction mixture was concentrated under reduced pressure toa minimum volume, Et₂O was added, and the resulting suspension stirredfor 16 hours. The solid was collected by filtration and dried under highvacuum to provide(S)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propan-1-amine,dihydrochloride as a yellowish solid (Compound 2025, 10.55 g, 100%yield): ¹H NMR (300 MHz, CDCl₃) δ 7.80 (d, 1H), 7.10 (d, 1H), 4.50 (m,2H), 4.40 (m, 2H), 3.40 (m, 1H), 3.00 (m, 2H), 1.25 (d, 3H).

As shown in step 7-v of Scheme 7,(S)-2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propan-1-amine,dihydrochloride (10.0 g, 49.5 mmol), 4,6-dichloropyrimidine (8.11 g,54.5 mmol), and TEA (15.03 g, 20.7 mL, 148.6 mmol) stirred in NMP (125mL) at 50° C. for 3.5 hours. The reaction mixture was cooled, 300 mL ofEtOAc was added, the organics washed with water, dried over Na₂SO₄,filtered, concentrated under reduced pressure, diluted with a minimumamount of DCM, and purified by medium pressure silica gel chromatography(0-100% EtOAc/hexanes). Fractions containing product were concentratedunder reduced pressure to yield an oil which was dissolved in hot MTBE.Cooling of the MTBE solution resulted in a precipitate which wascollected by filtration and suspended in 4:1 hexane/MTBE. Once again thesolid was collected by filtration to provide6-chloro-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]pyrimidin-4-amine(Compound 2026, 10.78 g, 71% yield): ESMS=307.21 (M+H); ¹H NMR (300 MHz,CDCl₃) δ 8.33 (s, 1H), 7.78 (d, J=7.1 Hz, 1H), 6.80 (d, J=7.1 Hz, 1H),6.40 (s, 1H), 4.44 (m, 2H), 4.34-4.21 (m, 2H), 3.50 (m, 3H), 1.31 (d,J=6.8 Hz, 3H).

A portion of6-chloro-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]pyrimidin-4-aminewas recrystallized from toluene and the resulting crystals analyzed byX-ray crystallography, confirming the (S)-configuration. X-ray powderdiffraction (XRPD) showed peaks at 8.75, 10.30, 14.15, 17.50, 18.30,18.80, 20.75, 20.95, 23.10, 23.95, 24.60, 26.20, 26.90, 29.20, 29.95,30.45, and 31.95 (2-theta scale).

As shown in step 7-vi of Scheme 7,6-chloro-N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl]pyrimidin-4-amine(410 mg) was dissolved in IPA (0.75 mL).N-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine(23 mg) was added, followed by the addition of 2M Na₂CO₃ (122 μL) and1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),dichloromethane complex (7 mg). The reaction vessel was sealed andheated at 80° C. overnight. The mixture was cooled, diluted with ethylacetate, washed with water, dried over Na₂SO₄, filtered, concentratedunder reduced pressure and purified by reversed-phase HPLC, 5-50%ACN/H₂O/0.1% TFA. Fractions containing pure product were collected,dissolved in MeOH, passed through a carbonate cartridge, andconcentrated under reduced pressure to provide(S)—N⁶-(2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl)-N²′-methyl-[4,5′-bipyrimidine]-2′,6-diamine(Compound 462): ESMS=380.39 (M+H); ¹H NMR (300 MHz, methanol-d4) δ 8.75(s, 2H), 8.47 (s, 1H), 7.65 (d, J=5.3 Hz, 1H), 6.94 (d, J=5.2 Hz, 1H),6.76 (s, 1H), 4.46-4.34 (m, 2H), 4.32-4.19 (m, 2H), 3.59 (ddd, J=12.0,11.5, 7.3 Hz, 3H), 2.99 (s, 3H), 1.32 (d, J=6.7 Hz, 3H).

Example 8. Preparation of(S)—N-(2-(2,3-dihydro-[1,4]dioxino[2,3-]pyridin-8-yl)propyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-amine(Compound 443)

As shown in step 8-i of Scheme 8,N-(2-bromoallyl)-6-(6-methyl-3-pyridyl)pyrimidin-4-amine (240 mg, 0.7792mmol, Compound 2027; which was prepared by reacting4-chloro-6-(6-methylpyridin-3-yl)pyrimidine with2-bromoprop-2-en-1-amine under basic conditions),8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine(287.0 mg, 1.091 mmol), and Na₂CO₃ (1.169 mL of 2 M, 2.338 mmol) werestirred in DMSO (5.945 mL). Pd(dppf)Cl₂ (63.63 mg, 0.07792 mmol) wasadded and the reaction mixture stirred at 100° C. for 1 hour, then at RTfor 16 hours. After this time the reaction mixture was partitionedbetween EtOAc and water, the organics dried over Na₂SO₄, filtered, andthe volatiles removed under reduced pressure. The residue was dissolvedin DCM and purified by medium pressure silica gel chromatography(20-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to produceN-(2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)allyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-amine(Compound 2028) as yellow oil: LCMS=362.37 (M+H). This material was usedas is in subsequent reactions.

As shown in step 8-ii of Scheme 8,N-[2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)allyl]-6-(6-methyl-3-pyridyl)pyrimidin-4-amine(150 mg, 0.4151 mmol) was dissolved in MeOH and the reaction mixture wasplaced under an atmosphere of H₂. After stirring for 2 hours, themixture was filtered, concentrated under reduced pressure, and purifiedby medium pressure silica gel chromatography (0-5% MeOH/DCM) to produceN-(2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-amine(Compound 2029): LCMS=364.39 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 9.00 (d,J=2.0 Hz, 1H), 8.63 (s, 1H), 8.20 (dd, J=8.1, 2.3 Hz, 1H), 7.81 (d,J=5.0 Hz, 1H), 7.27 (d, J=4.2 Hz, 1H), 6.82 (d, J=5.1 Hz, 1H), 6.71 (s,1H), 4.43 (dd, J=5.1, 3.0 Hz, 2H), 4.27 (dd, J=5.1, 3.0 Hz, 2H), 3.56(m, 3H), 2.62 (s, 3H), 1.32 (d, 3H).

As shown in step 8-ii of Scheme 8,N-(2-(2,3-dihydro-[1,4]dioxino[2,3-b]pyridin-8-yl)propyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-aminewas purified by supercritical fluid chromatography using a ChiralPak®IC™ column (10 mm×250 mm, 1/1 CO₂/EtOH, 35° C., 12 mL/min, 100 atm.)Fractions of the first eluting product with a retention time of 11.08min were combined to produce(S)—N-(2-(2,3-dihydro-[1,4]dioxino[2,3-]pyridin-8-yl)propyl)-6-(6-methylpyridin-3-yl)pyrimidin-4-amine(Compound 443).

Example 9. Preparation of(S)—N-methyl-8-(1-((2′-methyl-[4,5′-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide(Compound 578)

As shown in step 9-i of Scheme 9, to 4,6-dichloropyrimidine (265.3 g,1.781 mol) in 1.68 L DME was added CsF (241.5 g, 1.59 mol) and 700 mLwater. The mixture was flushed with nitrogen gas for 30 minutes andPd(PPh₃)₄ (22.05 g 19.08 mmol) was added. The resulting light yellowsolution was flushed with nitrogen gas for an additional 40 minutes,heated to reflux, and a nitrogen-flushed solution of2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (140g, 636.1 mmol in 420 mL DME) was added dropwise over 1.6 hours. Theresulting dark red solution was refluxed under an atmosphere of nitrogenfor 16 hours. After this time the mixture was cooled to RT and 300 mL ofwater was added. The mixture was then cooled to 5° C. and stirred for 40minutes. The resulting precipitate(6-chloro-2′-methyl-4,5′-bipyrimidine, compound 2039) was collected byfiltration, washed with 50 mL water, followed by washing with 150 mLEtOAc. The filtrate was separated into two layers and the aqueous layerextracted with EtOAc (2×1 L). The combined organics were dried overNa₂SO₄, concentrated under reduced pressure, diluted with 300 mL of DCM,and purified by medium pressure silica gel chromatography (0-100%EtOAc/DCM). Fractions containing pure product were concentrated underreduced pressure and the concentrate treated with 400 mL of hexanes toproduce compound 2039 as a solid. This material was combined with thesolid product previously collected and treated with 400 mL of 1:1THF/DCM. The resulting suspension was heated and transferred to afiltration funnel containing a plug of Florisil®. The plug was washedwith additional 1:1 THF/DCM to dissolve any remaining solid material andthen washed with 4:1 EtOAc/DCM (2×1 L). The combined filtrates wereconcentrated under reduced pressure to produce a pink solid which wastriturated with 500 mL hexanes, collected by filtration, and dried underreduced pressure to provide 6-chloro-2′-methyl-4,5′-bipyrimidine(compound 2039, 88.8 g, 68% yield): LC-MS=207.01 (M+H); ¹H NMR (300 MHz,CDCl₃) δ 9.30 (s, 2H), 9.10 (d, J=1.2 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H),2.85 (s, 3H).

As shown in step 9-ii of Scheme 9, 2-bromoaniline (520 g, 3.023 mol) wasmelted at 50° C. in an oven and then added to a reaction vesselcontaining stirring acetic acid (3.12 L). Methanesulfonic acid (871.6 g,588.5 mL, 9.069 mol) was then added over 15 minutes. The reactionmixture was heated to 60° C. and methyl vinyl ketone (377 mL, 1.5equiv.) was added over 5 minutes and the reaction mixture stirred for 1hour at 90° C. After this time another 50 mL (0.2 equiv.) of methylvinyl ketone was added and the reaction mixture stirred for anadditional 16 hours. The resulting dark brown solution was cooled withan ice-water bath and poured portion-wise into a stirring solution of50% w/w aq NaOH (3.894 L, 73.76 mol) and ice (1 kg) also cooled with anice-water bath. Additional ice was added as required during addition tomaintain the reaction temperature below 25° C. After addition wascomplete the reaction mixture (pH >10) was stirred for 30 minutes whilstcooling in an ice/water bath. A precipitate formed which was collectedby filtration, washed with water (2 L×3), and dissolved in DCM (4 L).The organics were washed with water (2 L) and the aqueous phaseback-extracted with DCM (1 L). The combined organics were dried overNa₂SO₄, filtered through a pad silica gel (about 2 L), eluted with DCMand then 3% EtOAc/DCM until all of the product came through the plug.The volatiles of the filtrate were removed at reduced pressure and theresidue was triturated with hexanes (about 500 mL). The resulting solidwas collected by filtration, washed with hexanes (4×500 mL), and driedunder vacuum to yield 8-bromo-4-methylquinoline (compound 2030, 363 g,54% yield) as a light tan solid: LC-MS=222.17 (M+H); ¹H NMR (300 MHz,CDCl₃) δ 8.91 (d, J=4.3 Hz, 1H), 8.06 (d, J=7.4 Hz, 1H), 7.99 (d, J=8.4Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.30 (d, J=4.2 Hz, 1H), 2.73 (s, 3H).

As shown in step 9-iii of Scheme 9, selenium dioxide (764.7 g, 6.754mol) was taken up in 3.25 L of dioxane and 500 mL of water. The stirredsolution was heated to 77° C. and 8-bromo-4-methylquinoline (compound2030, 500 g, 2.251 mol) was added in one portion. The reaction mixturewas stirred at reflux for 30 minutes and then cooled with a water bathto about 45° C., at which temperature a precipitate was observed. Thesuspension was filtered through diatomaceous earth which wassubsequently washed with the hot THF to dissolve any residual solids.The filtrate was concentrated to a minimum volume under reduced pressureand 2M NaOH (2.81 L, 5.63 mol) was added to achieve a pH of 8 to 9. Thereaction mixture was stirred at this pH for 30 minutes. A precipitateresulted which was collected by filtration and air-dried overnight toproduce 8-bromoquinoline-4-carbaldehyde (compound 2031) as an yellowishsolid: MS=236.16 (M+H); ¹H NMR (300 MHz, CDCl₃) δ 10.52 (s, 1H), 9.34(d, J=4.2 Hz, 1H), 9.05 (dd, J=8.5, 1.2 Hz, 1H), 8.18 (dd, J=7.5, 1.3Hz, 1H), 7.88 (d, J=4.2 Hz, 1H), 7.60 (dd, J=8.5, 7.5 Hz, 1H). Thismaterial was used as is in subsequent reactions.

As shown in step 9-iv of Scheme 9, to a stirred suspension of8-bromoquinoline-4-carbaldehyde (531.4 g, 2.25 mol) in THF (4.8 L) wasadded water (4.8 L) and monosodium phosphate (491.1 g, 4.05 mol). Themixture was cooled to 5° C. and, keeping the reaction temperature below15° C., sodium chlorite (534.4 g, 4.727 mol) was slowly addedportionwise as a solid over about 1 hour. After addition was completethe reaction mixture was stirred at 10° C. for 1 hour followed by theportionwise addition of IN Na₂S₂O₃ (1.18 L) whilst keeping thetemperature below 20° C. The reaction mixture was stirred at RT followedby the removal of the THF under reduced pressure. The resulting aqueoussolution containing a precipitate was treated with sat'd NaHCO₃ (about 1L) until a pH of 3 to 4 was achieved. This mixture was stirred anadditional 15 minutes and the solid was collected by filtration, washedwith water (2×1 L), washed with tert butyl methyl ether (2×500 mL), anddried in a convection oven at 60° C. for 48 hours. Additional dryingunder high vacuum provided 8-bromoquinoline-4-carboxylic acid (compound2032, 530.7 g, 94% yield from compound 1030) as a yellowish tan solid:LC-MS=252.34 (M+H); ¹H NMR (300 MHz, DMSO-d₆) δ 14.09 (s, 1H), 9.16 (d,J=4.4 Hz, 1H), 8.71 (dd, J=8.6, 1.2 Hz, 1H), 8.25 (dd, J=7.5, 1.2 Hz,1H), 8.03 (d, J=4.4 Hz, 1H), 7.64 (dd, J=8.6, 7.5 Hz, 1H).

As shown in step 9-v of Scheme 9, to a suspension of8-bromoquinoline-4-carboxylic acid (compound 2032, 779.4 g, 3.092 mol)in DCM (11.7 L) was added anhydrous DMF (7.182 mL, 92.76 mmol). Thereaction mixture was cooled to 10° C. and oxalyl chloride (413 mL, 4.638mol) was added dropwise over 30 minutes. The reaction mixture wasstirred an additional 30 minutes after addition was complete,transferred to an evaporation flask, and the volatiles removed underreduced pressure. Anhydrous THF (2 L) was added and the volatiles wereonce more removed under reduced pressure in order to remove any residualoxalyl chloride. Anhydrous THF was added to the residue under anatmosphere of nitrogen and the resulting suspension of intermediate8-bromoquinoline-4-carboxylic acid chloride was stored for later use.Separately, the original reaction flask was thoroughly flushed withnitrogen gas to remove any residual oxalyl chloride and the flaskcharged with dry THF (1.16 L). After cooling to 5° C., aqueous methylamine (2.14 L of 40% w/w MeNH₂/water, 24.74 mol) was added followed bythe addition of additional THF (1.16 L). To this solution was addedportionwise over 1 hour the intermediate acid chloride suspension,keeping the reaction mixture temperature below 20° C. during addition.The evaporation vessel used to store the acid chloride was rinsed withanhydrous THF and aqueous MeNH₂ (500 mL) and this added to the reactionmixture, which was allowed to come to room temperature over 16 hours.The organic volatiles were removed under reduced pressure and theremaining mostly aqueous suspension diluted with water (1.5 L). Thesolids were collected by filtration, washed with water until thefiltrate had a pH of less than 11, washed with MTBE (2×800 mL), anddried in a convection oven at 60° C. to provide8-bromo-N-methyl-quinoline-4-carboxamide (compound 2033, 740.4 g, 90%yield) as a light brown solid: LC-MS=265.04 (M+H); ¹H NMR (300 MHz,DMSO-d₆) δ 9.08 (d, J=4.3 Hz, 1H), 8.78 (d, J=4.7 Hz, 1H), 8.21 (dd,J=7.5, 1.2 Hz, 1H), 8.16 (dd, J=8.5, 1.3 Hz, 1H), 7.65 (d, J=4.3 Hz,1H), 7.58 (dd, J=8.5, 7.5 Hz, 1H), 2.88 (d, J=4.6 Hz, 3H).

As shown in step 9-vi of Scheme 9,8-bromo-N-methyl-quinoline-4-carboxamide (compound 2033, 722 g, 2.723mol) andtert-butyl-N-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]carbamate(compound 2034, 925.4 g, 3.268 mol) were combined in a reaction flask.Na₂CO₃ (577.2 g, 5.446 mol) was added followed by the addition of water(2.17 L). The mixture was stirred for 5 minutes, 1,4-dioxane (5.78 L)was added, and the mixture was deoxygenated by bubbling in a stream ofnitrogen gas for 30 minutes. Pd(dppf) Cl₂/DCM (44.47 g, 54.46 mmol) wasadded and deoxygenation was continued as before for an additional 30minutes. The reaction mixture was stirred at reflux for 16 hours,allowed to cool to 70° C., and water (5.42 L) was added. The mixture wascooled further with an ice-water bath and stirring continued at <10° C.for 2 hours. A precipitate resulted which was collected by filtration,washed with water (3×1 L), and washed with TBME (2×1 L). The resultingprecipitate cake was split into two equal portions. Each portion wasdissolved in THF/DCM (4 L) and poured onto a plug of Florisil® (3 Lfiltration funnel with about 1.5 L of florisil, using DCM to wet plug).The plug was subsequently washed with MeTHF until it was determined bythin layer chromatography analysis that no product remained in thefiltrate. The filtrates from both cake portions were combined andconcentrated under reduced pressure to give an orange solid. TBME (1 L)was added and the resulting suspension was filtered. The collected solidwas washed with 800 mL of TBME and dried under high vacuum overnight toprovide tert-butyl (2-(4-(methylcarbamoyl)quinolin-8-yl)allyl)carbamate(compound 2035, 653 g, 70% yield) as an off-white solid: LC-MS=342.31(M+H); ¹H NMR (300 MHz, CDCl₃) δ 8.93 (d, J=4.3 Hz, 1H), 8.17 (dd,J=8.4, 1.6 Hz, 1H), 7.68-7.53 (m, 2H), 7.41 (d, J=4.3 Hz, 1H), 6.09 (br.s, 1H), 5.54 (s, 1H), 5.28 (s, 1H), 5.10 (br. s, 1H), 4.33 (d, J=6.0 Hz,2H), 3.11 (d, J=4.8 Hz, 3H), 1.38 (s, 9H). Additional product (34.9 g,74% total yield) was obtained by concentrating the filtrate underreduced pressure, dissolving the residue in THF, filtering the solutionthrough a plug of Florisil® as before, washing the plug with MeTHF,concentrating the filtrate under reduced pressure, adding 250 mL ofTBME, stirring for 0.5 hours, collecting the resulting precipitate byfiltration, washing the solid with EtOAc (40 mL), acetonitrile (50 mL),and drying the solid under high vacuum overnight.

As shown in step 9-vii of Scheme 9, to a stirring suspension oftert-butyl (2-(4-(methylcarbamoyl)quinolin-8-yl)allyl)carbamate(compound 2035, 425 g, 1.245 mol) in EtOH (4.25 L) was added 5.5M HCl iniPrOH (1.132 L, 6.225 mol). The reaction mixture was stirred at reflux(76° C. internal temp) for 30 minutes and then over 90 minutes while itwas allowed to cool to 40° C. EtOAc (2.1 L) was added and the mixturewas stirred for an additional 2 hours. The solid was collected byfiltration, washed with EtOAc, and dried under high vacuum to provide8-[1-(aminomethyl)vinyl]-N-methyl-quinoline-4-carboxamide,dihydrochloride (compound 2036, 357.9 g, 91% yield) as a tan solid:LC-MS=242.12 (M+H); ¹H NMR (300 MHz, methanol-d₄) δ 9.07 (d, J=4.6 Hz,1H), 8.27 (dd, J=8.5, 1.5 Hz, 1H), 7.89 (dd, J=7.2, 1.5 Hz, 1H),7.81-7.72 (m, 2H), 5.85 (s, 1H), 5.75 (s, 1H), 4.05 (s, 2H), 3.04 (s,3H).

As shown in step 9-viii of Scheme 9,8-[1-(aminomethyl)vinyl]-N-methyl-quinoline-4-carboxamide,dihydrochloride (compound 2036, 168.8 g, 537 mmol) was stirred in MeOH(1.688 L) and TEA (114.2 g, 157.3 mL, 1.129 mol) was added, followed bythe addition of 5% Pd on BaSO₄ (22.88 g, 10.75 mmol). The atmosphere ofthe reaction mixture was replaced with hydrogen gas and the reactionstirred at under 1 atmosphere of hydrogen atmosphere for 16 hours. Afterthis time, the hydrogen atmosphere was removed and the mixture filteredthrough diatomaceous earth, concentrated under reduced pressure, andtreated with 800 mL water and 250 mL DCM. The resulting biphasic mixturewas stirred vigorously until most of the solids had dissolved, resultingin a thick mixture that separates on standing. The pH of the aqueouslayer was checked and found to be pH=8. This layer was washed with 3×500mL DCM, the pH adjusted to 14 with 500 mL 6N NaOH, and extracted with anadditional 500 mL DCM. The aqueous solution was then treated with 500 gNaCl and it was extracted with an additional 500 mL DCM. The combinedorganics were dried over Na₂SO₄, filtered, and concentrated underreduced pressure to provide8-(1-aminopropan-2-yl)-N-methylquinoline-4-carboxamide [compound 2037(racemic mixture) 104.2 g, 80% yield]: LC-MS=244.43 (M+H); ¹H NMR (300MHz, methanol-d₄) δ 8.94 (d, J=4.3 Hz, 1H), 8.02 (dd, J=8.3, 1.6 Hz,1H), 7.72-7.59 (m, 2H), 7.50 (d, J=4.3 Hz, 1H), 4.30 (h, J=7.0 Hz, 1H),3.04 (dd, J=12.7, 7.0 Hz, 1H), 3.01 (s, 3H), 2.90 (dd, J=12.7, 6.9 Hz,1H), 1.40 (d, J=7.1 Hz, 3H).

As shown in step 9-ix of Scheme 9, the two racemates of8-(1-aminopropan-2-yl)-N-methylquinoline-4-carboxamide (compound 137,1380.5 g) were separated by chiral HPLC. Accordingly, 260 mL aliquots ofracemic mixture (6 mg/mL) were loaded onto a Chiralpak AY™ column (11cm×25 cm) and eluted with acetonitrile (0.2% TEA) at a flow rate of 400mL/minute. Two major peaks eluted. Peak 1 had a retention time of 7.7min. and peak 2 had a retention time of 12.2 min. when analyzed by HPLC(Chiralpak AY-H™ column (4.6 mm×250 mm) eluted with acetonitrile (0.1%isopropylamine) at a flow rate of 1 mL/min). The combined peak 2fractions were collected and the volatiles removed under reducedpressure to produce8-[(1S)-2-amino-1-methyl-ethyl]-N-methyl-quinoline-4-carboxamide (578.3g, 97.4% enantiomeric excess): specific rotation (10 mg/mL in MeOH, 100mm cell)=+24.20; LC-MS=244.19 (M+H); ¹H NMR (300 MHz, methanol-d₄) δ8.94 (d, J=4.3 Hz, 1H), 8.02 (dd, J=8.3, 1.6 Hz, 1H), 7.72-7.59 (m, 2H),7.50 (d, J=4.3 Hz, 1H), 4.30 (h, J=7.0 Hz, 1H), 3.05 (dd, J=12.8, 7.1Hz, 1H), 3.01 (s, 3H), 2.90 (dd, J=12.7, 6.9 Hz, 1H), 1.40 (d, J=7.0 Hz,3H). The HCl salt was formed by adding 5N HCl/IPA (220 mL, 1.100 mol) toan ice-bath cooled stirring solution of8-[(1S)-2-amino-1-methyl-ethyl]-N-methyl-quinoline-4-carboxamide (244.5g, 1.005 mmol) in 980 mL of 1:1 MeOH/DCM. The ice bath was removed and1470 mL of Et₂O was added portionwise. The precipitate was collected byfiltration, washed with Et₂O and dried under high vacuum to produce8-[(1S)-2-amino-1-methyl-ethyl]-N-methyl-quinoline-4-carboxamide,hydrochloride (compound 2038, 275.8 g 98.1% yield).

As shown in step 9-x of Scheme 9, to a stirring solution of4-chloro-6-(2-methylpyrimidin-5-yl)pyrimidine (compound 2039, 60 g,290.4 mmol) and8-[(1S)-2-amino-1-methyl-ethyl]-N-methyl-quinoline-4-carboxamide,hydrochloride (compound 2038, 82.87 g, 296.2 mmol) in THF (600 mL) wasadded water (168.0 mL) and then 2M Na₂CO₃ (aq.) (363 mL, 726.3 mmol).The reaction mixture was stirred at reflux for 16 hours. A precipitateresulted which was solubilized by the addition of 2M HCl. The solutionwas washed with DCM (3×500 mL) followed by slow addition of 6M NaOH toachieve a pH of 7. The reaction mixture was stirred for 1 hour at RT.The resulting precipitate was collected by filtration and washed withwater (4×250 mL) and IPA (4×125 mL). The solid was then dried under highvacuum at 50° C. for 16 hours to produce(S)—N-methyl-8-(1-((2′-methyl-[4,5′-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide(compound 578, 102 g, 85% yield) as a light tan solid: LC-MS=414.40(M+H); ¹H NMR (300 MHz, DMSO-d₆, 70° C.) δ 9.14 (s, 2H), 8.95 (d, J=4.3Hz, 1H), 8.47 (s, 1H), 8.34 (br. s, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.74(d, J=7.3 Hz, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.50 (d, J=4.3 Hz, 1H), 7.28(br. s, 1H), 7.04 (s, 1H), 4.52 (h, J=7.0 Hz, 1H), 3.83-3.66 (m, 2H),2.88 (d, J=4.4 Hz, 3H), 2.68 (s, 3H), 1.42 (d, J=6.9 Hz, 3H).

Example 10. Preparation of(S)—N-methyl-8-(1-((2′-methyl-4′,6′-dideutero-[4,5′-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide(Compound 844)

As shown in step 10-i of Scheme 10, tert-butyl(2-(4-(methylcarbamoyl)quinolin-8-yl)allyl)carbamate (compound 2035, 83g, 243.1 mmol) was taken up in EtOH and stirred for 10 minutes. To thesolution was added HCl/i-PrOH (5M, 194.5 mL, 972.4 mmol) at RT. Thereaction mixture was warmed to 60° C. and stirred for 2 hours. Aftercooling, the mixture was concentrated under reduced pressure followed byazeotropic removal of trace water with toluene under reduced pressure.Trituration with EtOAc afforded a tan solid (74 g) which was dissolvedin a mixture of water/THF (415 mL/300 mL). Sodium bicarbonate (61.27 g,729.3 mmol) was added portionwise at RT and the reaction mixture stirredfor 10 minutes after the addition was complete. After cooling to 0° C.,acetic anhydride (68.81 mL, 74.45 g, 729.3 mmol) in THF (120 mL) wasadded dropwise. The reaction mixture was allowed to come to RT andstirred for 12 hours. Dilution with water produced a white solid whichwas collected by filtration and washed with MTBE (2×500 mL). Thefiltrate was extracted with EtOAc (4×500 mL) and the combined extractswashed with brine (100 mL), dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was triturated withMTBE (500 mL) and the resulting solid combined with the solid collectedby filtration to provide8-(3-acetamidoprop-1-en-2-yl)-N-methylquinoline-4-carboxamide (compound2040, 42.4 g total, 62% yield) as an off-white solid: ¹H NMR (300 MHz,DMSO-d₆) δ 8.96 (d, J=4.3 Hz, 1H), 8.72 (d, J=4.5 Hz, 1H), 8.21-7.96 (m,2H), 7.69-7.56 (m, 2H), 7.53 (d, J=4.3 Hz, 1H), 5.35 (d, J=1.5 Hz, 1H),5.16 (s, 1H), 4.30 (d, J=5.9 Hz, 2H), 2.87 (d, J=4.6 Hz, 3H), 1.80 (s,3H).

As shown in step 10-ii of Scheme 10, under an atmosphere of nitrogen8-(3-acetamidoprop-1-en-2-yl)-N-methylquinoline-4-carboxamide (12.4 g,43.77 mmol) andcycloocta-1,5-diene/(2R,5R)-1-[2-[(2R,5R)-2,5-diethylphospholan-1-yl]phenyl]-2,5-diethylphospholane:rhodium(+1) cation-trifluoromethanesulfonate(Rh(COD)(R,R)-Et-DuPhos-OTf, 316.3 mg, 0.4377 mmol) in methanol (372.0mL) were combined and warmed to 35-40° C. until the solids weresolubilized. The reaction mixture was placed in a hydrogenationapparatus, the atmosphere replaced with hydrogen, and the mixtureagitated under 100 p.s.i. of hydrogen at 50° C. for 14 hours. Aftercooling to RT, the mixture was filtered through a bed of Florisil®,which was subsequently washed with MeOH (2×50 mL). The filtrate wasconcentrated under reduced pressure and any trace water removed via aDCM azeotrope under reduced pressure. The residue was triturated with20% DCM in MTBE (2×100 mL) to afford(S)-8-(1-acetamidopropan-2-yl)-N-methylquinoline-4-carboxamide (compound2041, 11.0 g, 88% yield, 96% e.e.) as an off-white solid: ¹H-NMR (300MHz, DMSO-d₆) δ 8.97 (d, J=4.3 Hz, 1H), 8.67 (d, J=4.7 Hz, 1H), 7.97(dd, J=8.1, 1.5 Hz, 1H), 7.88 (t, J=5.6 Hz, 1H), 7.73-7.54 (m, 2H), 7.52(d, J=4.3 Hz, 1H), 4.31 (dd, J=14.3, 7.1 Hz, 1H), 3.55-3.32 (m, 3H),2.86 (d, J=4.6 Hz, 3H), 1.76 (s, 3H), 1.28 (d, J=7.0 Hz, 3H). Theenantiomeric excess (e.e.) was determined by chiral HPLC (ChiralPac IC,0.46 cm×25 cm], flow rate 1.0 mL/min for 20 min at 30° C. (20:30:50methanol/ethanol/hexanes and 0.1% diethylamine) with a retention timefor the (R)-enantiomer of 5.0 min, and for the (S)-enantiomer of 6.7min.

As shown in step 10-iii of Scheme 10,(S)-8-(1-acetamidopropan-2-yl)-N-methylquinoline-4-carboxamide (11.0 g,38.55 mmol) in 6M aqueous HCl (192.7 mL, 1.156 mol) was warmed to 60° C.After stirring for 2 days at this temperature, the reaction mixture wascooled and an additional 20 mL of 6M HCl was added. Stirring wascontinued for an additional 2 days at 70° C. The reaction mixture wascooled with an ice bath and the pH adjusted to about 11 with 6M NaOH(aq). The aqueous mixture was extracted with 5% MeOH/DCM and thecombined organic extracts washed with water (60 mL), brine (100 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford crude product as a tan solid. This solid wassuspended in EtOAc (200 mL), cooled to 3° C. with an ice bath, and 6MHCl/i-PrOH (30 mL) was added portionwise to produce a white precipitatewhich was collected by filtration. The solid was washed with EtOAc (100mL) and dried under high vacuum to provide(S)-8-(1-aminopropan-2-yl)-N-methylquinoline-4-carboxamide,dihydrochloride [compound 2038, 7.8 g, 61% yield, 95% purity (5%compound 2041)] as a white solid. This material was used as is insubsequent reactions.

As shown in step 10-iv of Scheme 10,8-[(1S)-2-amino-1-methyl-ethyl]-N-methyl-quinoline-4-carboxamide,hydrochloride (compound 2038, 24.0 g, 72.86 mmol) was taken up in THF(230 mL) and water (40 mL) and stirred for 5 minutes. Sodium carbonate(15.44 g, 145.7 mmol) in 100 mL of water was added and the reactionmixture stirred for 10 minutes. 4,6-Dichloropyrimidine (12.18 g, 80.15mmol) was added and the reaction mixture heated at reflux at 66° C. for2 hours. The reaction mixture was cooled to RT, diluted with 200 mL ofEtOAc, the organic layer separated, and the aqueous layer extracted with100 mL EtOAc. The combined organics were washed with water (60 mL),brine (100 mL), dried over Na2SO4, filtered through a bed of silica gel(100 g), and concentrated under reduced pressure. The resulting crudeproduct was triturated with 20% DCM in MBTE (200 mL) then MBTE (200 mL)to produce(S)-8-(1-((6-chloropyrimidin-4-yl)amino)propan-2-yl)-N-methylquinoline-4-carboxamide(compound 2042, 23.15 g, 88% yield) as a white solid: ¹H NMR (300 MHz,DMSO-d₆, 70° C.) δ 8.97 (d, J=4.3 Hz, 1H), 8.38 (s, 1H), 8.20 (s, 1H),8.03 (d, J—8.5 Hz, 1H), 7.71 (d, J=6.8 Hz, 1H), 7.66-7.55 (m, 1H), 7.52(d, J=4.2 Hz, 2H), 6.63 (s, 1H), 4.46 (dd, J=14.1, 7.1 Hz, 1H), 3.67 (s,2H), 2.90 (d, J=4.6 Hz, 3H), 1.40 (d, J=7.0 Hz, 3H); [α]_(D) ²⁴=44.77(c=1.14, MeOH).

As shown in step 10-v of Scheme 10, to a solution of4,6-dichloro-2-methyl-pyrimidin-5-amine (14.04 g, 78.88 mmol) stirred inmethanol-d₄ (140.4 mL) was added formic acid-d₂ (7.77 g, 161.7 mmol) andPd black (765 mg, 7.19 mmol, wetted in methanol-d₄), followed bytriethylamine (16.36 g, 22.53 mL, 161.7 mmol). The reaction mixture wassealed in a tube and stirred at RT overnight. The mixture was thenfiltered and concentrated under reduced pressure. Et₂O (250 mL) wasadded and the mixture stirred for 1 hour at RT. The resulting solidswere filtered and washed with Et₂O (×2). The filtrate was concentratedunder reduced pressure to yield 4,6-dideutero-2-methyl-pyrimidin-5-amine(compound 2043, 5.65 g, 65% yield) as a light yellow solid: 1H NMR (300MHz, DMSO-d₆) δ 5.25 (s, 2H), 2.40 (s, 3H). This compound was used insubsequent steps without further purification.

As shown in step 10-vi of Scheme 10, to4,6-dideutero-2-methyl-pyrimidin-5-amine (5.35 g, 48.14 mmol) in CH₃CN(192.5 mL) was added dibromocopper (16.13 g, 3.38 mL, 72.21 mmol)followed by t-butylnitrite (8.274 g, 9.54 mL, 72.21 mmol). After 1 hour,the reaction was filtered through diatomaceous earth withdichloromethane. The filtrate was washed with water/brine (1:1), theorganic layer separated, the aqueous layer extracted withdichloromethane (2×), and the combined organic layers filtered throughdiatomaceous earth and concentrated under reduced pressure. The crudeproduct was purified by medium pressure silica gel column chromatography(0-10% EtOAc/hexanes) to yield 5-bromo-4,6-dideutero-2-methyl-pyrimidine(compound 2044, 4.1 g, 49% yield): ¹H NMR (300 MHz, methanol-d₄) δ 2.64(s, 3H).

As shown in step 10-vii of Scheme 10, a mixture of5-bromo-4,6-dideutero-2-methyl-pyrimidine (8.5 g, 48.57 mmol),bis(pinacolato)diboron (13.57 g, 53.43 mmol), and KOAc (14.30 g, 145.7mmol) in 2-methyltetrahydrofuran (102.0 mL) was degassed by flushingwith nitrogen. To this was addeddichloro-bis(tricyclohexylphosphoranyl)-palladium (PdCl₂[P(cy)₃]₂, 1.01g, 1.364 mmol) and the reaction mixture stirred in a sealed tubeovernight at 100° C. The mixture was filtered and the filtrate stirredwith Silabond® DMT silica (SiliCycle, Inc., 0.58 mmol/g, 3.53 g) for 1hour. The mixture was filtered and concentrated under reduced pressureto yield2-methyl-4,6-dideutero-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(compound 2045, 13.6 g, 72% purity, the major contaminant being pinacol)as a light yellow oil: ¹H NMR (300 MHz, CDCl₃) δ 2.75 (s, 3H), 1.30 (s,12H). This compound was used in subsequent steps without furtherpurification.

As shown in step 10-viii of Scheme 10,(S)-8-(1-((6-chloropyrimidin-4-yl)amino)propan-2-yl)-N-methylquinoline-4-carboxamide(2.542 g, 7.146 mmol),2-methyl-4,6-dideutero-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(2.204 g, 7.146 mmol, 72% by weight), Na₂CO₃ (10.72 mL of 2 M (aq.),21.44 mmol), and Silacat® DPP Pd (SiliCycle, Inc., 1.429 g, 0.3573 mmol)were taken up in dioxane (30.00 mL), the solution flushed with nitrogengas for 5 min, and the reaction mixture stirred at 90° C. for 16 hours.The mixture was filtered through diatomaceous earth, concentrated underreduced pressure, dissolved in DMSO, and purified by reversed-phasechromatography (10-40% CH₃CN/H₂O, 0.1% TFA). The product fractions werecombined and DCM and MeOH were added, followed by the addition of INNaOH until a pH of greater than 7 was obtained. The product solution wasextracted DCM (2×) and the combined extracts dried over Na₂SO₄,filtered, and concentrated under reduced pressure to yield(S)—N-methyl-8-(1-((2′-methyl-4′,6′-dideutero-[4,5′-bipyrimidin]-6-yl)amino)propan-2-yl)quinoline-4-carboxamide(Compound 844, 181 mg, 28% yield) as an off-white solid: ¹H NMR (300MHz, DMSO-d₆, 70° C.) δ 8.95 (d, J=4.2 Hz, 1H), 8.47 (s, 1H), 8.35 (s,1H), 8.01 (d, J=8.4 Hz, 1H), 7.74 (d, J=7.1 Hz, 1H), 7.59 (t, J=7.8 Hz,1H), 7.50 (d, J=4.3 Hz, 1H), 7.30 (s, 1H), 7.03 (s, 1H), 4.51 (h, J=7.2Hz, 1H), 3.78 (m, 2H), 2.88 (d, J=4.6 Hz, 3H), 2.68 (s, 3H), 1.41 (d,J=7.0 Hz, 3H).

Example 11. Preparation of(S)—N-methyl-8-(1-((6-(6-methylpyridin-3-yl)pyrimidin-4-yl)amino)propan-2-yl)quinazoline-4-carboxamide(Compound 971)

As shown in step 11-i of Scheme 11, 1-(2-amino-3-hydroxyphenyl)ethanone(4.0 g, 26.5 mmol) and formamide (20 mL, 45 mmol) were heated at 180° C.under microwave irradiation for 45 minutes. After cooling, water wasadded and the reaction mixture concentrated under reduced pressure. Theresidue was purified by medium pressure silica gel chromatography (2%MeOH/DCM) to produce 4-methylquinazolin-8-ol (compound 2046, 3.81 g, 90%yield) as a yellow solid. This product was used as is in subsequentreactions.

As shown in step 11-ii of Scheme 11, to a solution of4-methylquinazolin-8-ol (4.87 g, 30.40 mmol) in DCM at 0° C. was addedcesium carbonate (9.9 g, 40 mmol) andN-phenyl-bis(trifluoromethanesulfinimde (PhN(Tf)₂,14.12 g, 39.52 mmol).The cooling bath was removed and the reaction mixture was stirredovernight at RT. The organics were washed with water, 5% HCl, then 5%NaHCO3. The combined aqueous washes were back-extracted with DCM (3×)and the combined organics dried over Na₂SO₄, filtered, and purified bymedium pressure silica gel chromatography (0-50% EtOAc/hexanes) toprovide 4-methylquinazolin-8-yl trifluoromethanesulfonate (compound2047, 8.60 g, 93% yield) as a brown solid: ¹H-NMR (300 MHz, CDCl₃) δ9.33 (s, 1H), 8.17 (dd, J=8.4, 1.3 Hz, 1H), 7.82 (dd, J=7.9, 1.3 Hz),7.70 (t, J—8.1 Hz), 3.02 (s, 3H); 19F-NMR (282 MHz, CDCl₃) δ −73.5.

As shown in step 11-iii of Scheme 11, 4-methylquinazolin-8-yltrifluoromethanesulfonate (1.19 g, 4.07 mmol) and selenium dioxide (1.0g, 9.0 mmol) were taken up in 15 mL pyridine and the reaction mixturestirred at 60° C. for 4 hours. The reaction mixture was diluted with 100mL of THF and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 3.1 g, 8.14 mmol) was added. After stirringat RT for 30 minutes, a 2M methylamine/THF solution (5.0 mL, 10.0 mmol)was added. The reaction mixture was stirred at RT for 1 hour and thevolatiles removed under reduced pressure. The residue was taken up inDCM and washed with saturated NH₄Cl. The aqueous wash was back-extractedwith DCM (2×) and the combined organics dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. The residue was purified by mediumpressure silica gel chromatography (0-100% DCM/hexane) to provide4-(methylcarbamoyl)quinazolin-8-yl trifluoromethanesulfonate (compound2048, 982 g, 72% yield) as a yellowish solid: LC-MS=335.88 (M+H); ¹H NMR(300 MHz, CDCl₃) δ 9.65 (dd, J=8.6, 1.4 Hz, 1H), 9.47 (s, 1H), 8.27 (s,1H), 7.89 (dd, J=7.7, 1.3 Hz, 1H), 7.79 (dd, J=8.6, 7.8 Hz, 1H), 3.13(d, J=5.1 Hz, 3H); 19F-NMR (282 MHz, CDCl₃) δ −73.5.

As shown in step 11-iv of Scheme 11, A nitrogen-flushed solution oftert-butylN-[2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)allyl]carbamate(compound 2034, 990 mg, 3.5 mmol), 4-(methylcarbamoyl)quinazolin-8-yltrifluoromethanesulfonate (980 mg, 2.9 mmol) Na₂CO₃ (3 mL of 2 M (aq),5.9 mmol) and Pd(dppf)Cl₂ (119 mg, 0.14 mmol) in DMF (35 ml) was heatedat 100° C. for 3 h. After cooling to RT, the reaction mixture was pouredinto water and extracted with EtOAc (3×). The extracts were washed withbrine (2×). The aqueous phase was re-extracted with EtOAc, and theorganic extract washed with brine (2×). The combined organics were driedover Na₂SO₄, filtered, and concentrated under reduced pressure. Theresidue was purified by medium pressure silica gel chromatography(EtOAc/hexane 0-50%) to provide tert-butyl(2-(4-(methylcarbamoyl)quinazolin-8-yl)allyl)carbamate (compound 2049,392 mg, 39% yield) as a yellowish solid. LC-MS=343.13 (M+H); ¹H NMR (300MHz, Chloroform-d) δ 9.47 (dd, J=8.6, 1.4 Hz, 1H), 9.30 (s, 1H),8.31-8.12 (m, 1H), 7.91 ? 7.81 (m, 1H), 7.69 (dd, J=8.7, 7.1 Hz, 1H),5.57 (s, 1H), 5.31 (s, 1H), 5.02 (d, J=8.1 Hz, 1H), 4.36 (dd, J=5.3, 2.0Hz, 2H), 3.10 (d, J=5.1 Hz, 3H), 1.37 (s, 9H).

As shown in step 11-v of Scheme 11, a solution of tert-butylN-[2-[4-(methylcarbamoyl)quinazolin-8-yl]allyl]carbamate (200 mg, 0.58mmol) in DCM (10 mL) was treated with TFA (2 mL). After stirring for 2hours at RT, the reaction mixture was concentrated under reducedpressure and dried under high vacuum to provide8-[1-(aminomethyl)vinyl]-N-methyl-quinazoline-4-carboxamide,trifluroacetate (compound 2050, 207 mg, 100% yield): LC-MS=243.07 (M+H).This product was used in subsequent reactions as is.

As shown in step 11-vi of Scheme 11, to a suspension of4-chloro-6-(6-methyl-3-pyridyl)pyrimidine (70 mg, 0.289 mmol),8-[1-(aminomethyl)vinyl]-N-methyl-quinazoline-4-carboxamide,trifluroacetate (70 mg, 0.20 mmol) and Na₂CO₃ (92 mg, 0.86 mmol) washeated at 100° C. for 60 hours. After cooling, the volatiles wereremoved under reduced pressure, the residue dissolved in DCM, and theorganics washed with water. The aqueous phase was back-extracted withDCM (2×) and the combined organics dried over Na₂SO₄, filtered, andconcentrated, and concentrated under reduced pressure. The residue waspurified by medium pressure silica gel flash chromatography (0-6%MeOH/DCM) to give to provideN-methyl-8-(3-((6-(6-methylpyridin-3-yl)pyrimidin-4-yl)amino)prop-1-en-2-yl)quinazoline-4-carboxamide(compound 2051, 48 mg, 58% yield): LC-MS=412.09 (M+H); ¹H NMR (300 MHz,CDCl₃) δ 9.46 (dd, J=8.7, 1.5 Hz, 1H), 9.35 (s, 1H), 9.03 (d, J=2.4 Hz,1H), 8.61 (d, J=1.1 Hz, 1H), 8.39-8.14 (m, 2H), 7.84 (dd, J=7.1, 1.5 Hz,1H), 7.68 (dd, J=8.7, 7.1 Hz, 1H), 7.27 (d, J=8.1 Hz, 1H), 7.13 (s, 1H),6.24-5.93 (m, 1H), 5.59 (d, J=1.6 Hz, 1H), 4.64 (d, J=6.3 Hz, 2H), 3.09(d, J=5.1 Hz, 3H), 2.63 (s, 3H).

As shown in step 11-vii of Scheme 11,N-methyl-8-(3-((6-(6-methylpyridin-3-yl)pyrimidin-4-yl)amino)prop-1-en-2-yl)quinazoline-4-carboxamide(48 mg, 0.12 mmol) in MeOH (2 mL) and Rh(COD)(R,R)-Et-DuPhos-OTf (3 mg)were combined in a glass tube. The reaction mixture was flushed withhydrogen gas then stirred under an atmosphere of 100 psi hydrogen for 24hours at 60° C. in a stainless steel Parr high pressure reactor. Aftercooling and replacing the reaction atmosphere with nitrogen, thereaction mixture was filtered through Fluorisil®, the filtrateconcentrated under reduced pressure, and the residue purified by mediumpressure silica gel chromatography (0-5% MeOH/DCM) to provide(S)—N-methyl-8-(1-((6-(6-methylpyridin-3-yl)pyrimidin-4-yl)amino)propan-2-yl)quinazoline-4-carboxamide(compound 971, 25 mg, 49% yield): LC-MS=414.07 (M+H); ¹H NMR (400 MHz,methanol-d₄) δ 9.29 (s, 1H), 8.86 (br. s, 1H), δ 8.80 (dd, J=8.6, 1.3Hz, 1H), 8.37 (d, J=1.1 Hz, 1H), 8.14 (s, 1H), 8.04-7.87 (m, 1H), 7.71(dd, J=8.6, 7.2 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 6.71 (br. s, 1H), 4.51(q, J=7.1 Hz, 1H), 4.10-3.60 (m, 2H), 3.01 (s, 3H), 2.58 (s, 3H), 1.48(d, J=7.0 Hz, 3H).

Example 12. Preparation of(S)—N-methyl-8-(1-((2′-methyl-4′,6′-dideutero-[4,5′-bipyrimidin]-6-yl)amino)propan-2-yl)quinazoline-4-carboxamide(Compound 984)

As shown in step 12-i of Scheme 12,8-[1-(aminomethyl)vinyl]-N-methyl-quinazoline-4-carboxamide,trifluoroacetate (850 mg, 2.39 mmol) was dissolved in THF (30 mL). Thesolution was treated with Et₃N (2.4 mL, 17.5 mmol) and trifluoroaceticanhydride (0.5 mL, 3.8 mmol). The reaction mixture was stirred for 15hours at RT. The volatiles were removed under reduced pressure and theresidue suspended in water, extracted with EtOAc (3×), and the combinedorganics dried over Na₂SO₄, filtered, and concentrated under reducedpressure. The residue was purified by medium pressure silica gelchromatography (0-100% EtOAc/hexanes) to provideN-methyl-8-(3-(2,2,2-trifluoroacetamido)prop-1-en-2-yl)quinazoline-4-carboxamide(compound 2052, 783 mg, 97% yield): LC-MS=338.99 (M+H). This materialwas used in subsequent reactions as is.

As shown in step 12-ii of Scheme 12,N-methyl-8-(3-(2,2,2-trifluoroacetamido)prop-1-en-2-yl)quinazoline-4-carboxamide(700 mg, 2.07 mmol) in MeOH (35 mL) and Rh(COD)(R,R)-Et-DuPhos-OTf (50mg) were placed in a glass tube. The reaction mixture was flushed withhydrogen gas and stirred under an atmosphere of 100 psi hydrogen for 24hours at 60° C. in a stainless steel Parr high pressure reactor. Aftercooling, the reaction atmosphere was flushed with nitrogen. The reactionmixture was filtered through Fluorisil®, the filtrate concentrated underreduced pressure, and the residue purified by medium pressure silica gelchromatography (0-100% EtOAc/hexanes) to provide(S)—N-methyl-8-(1-(2,2,2-trifluoroacetamido)propan-2-yl)quinazoline-4-carboxamide(compound 2053, 317 mg, 45% yield): LC-MS=338.99 (M+H).

As shown in step 12-iii of Scheme 12, a solution of(S)—N-methyl-8-(1-(2,2,2-trifluoroacetamido)propan-2-yl)quinazoline-4-carboxamide(200 mg, 0.588 mmol), K₂CO₃ (406 mg, 2.94 mmol) in MeOH (10 mL) andwater (0.5 mL) was heated at 60° C. for 1 hour. The reaction mixtureconcentrated under reduced pressure and dried under high vacuum toprovide (S)-8-(1-aminopropan-2-yl)-N-methylquinazoline-4-carboxamide(compound 2054). LC-MS: 245.09 (M+), which was used in the followingreaction as is.

As shown in step 12-iv of Scheme 12, compound 2054 was suspended iniPrOH (10 mL) and 4,6-dichloropyrimidine (130 mg, 0.80 mmol) was added.The suspension was heated at 90° C. for 1 hour. After cooling, thevolatiles were removed under reduced pressure. The residue was dissolvedin EtOAc, washed with water, and the aqueous phase back-extracted withEtOAc (2×). The combined organics were dried over Na₂SO₄, filtered,concentrated under reduced pressure, and purified by medium pressuresilica gel chromatography (0-50% EtOAc/hexanes) to provide(S)-8-(1-((6-chloropyrimidin-4-yl)amino)propan-2-yl)-N-methylquinazoline-4-carboxamide(compound 2055, 153 mg, 73% yield): LC-MS=354.97, 357.00 (M+H); ¹H NMR(300 MHz, CDCl₃) δ 9.55-9.16 (m, 2H), 8.27-8.07 (m, 2H), 7.87-7.70 (m,1H), 7.61 (ddd, J=8.7, 7.2, 3.8 Hz, 1H), 4.35 (q, J=7.0 Hz, 1H), 3.49(m, 1H), 3.02 (dd, J=5.1, 1.7 Hz, 3H), 1.42 (d, J=7.0 Hz, 3H).

As shown in step 12-v of Scheme 12, a mixture of(S)-8-(1-((6-chloropyrimidin-4-yl)amino)propan-2-yl)-N-methylquinazoline-4-carboxamide(60 mg, 0.27 mmol),2-methyl-4,6-dideuterium-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine(compound 2042, 96 mg, 0.27 mmol), 2M Na₂CO₃ (aq) (0.3 mL), andPd(dppf)Cl₂ (8 mg) in dioxane (5 mL) were heated under microwaveirradiation at 110° C. for 1 hour. The volatiles were removed underreduced pressure and the residue suspended in water and extracted withEtOAc (3×). The combined organics were dried over Na₂SO₄, filtered,concentrated under reduced pressure, and the residue purified by mediumpressure silica gel chromatography (0-100% EtOAc/hexanes) to provide(S)—N-methyl-8-(1-((2′-methyl-4′,6′-dideutero-[4,5′-bipyrimidin]-6-yl)amino)propan-2-yl)quinazoline-4-carboxamide(Compound 984, 85 mg, 71%): LC-MS=417.13 (M+H); ¹H NMR (300 MHz,methanol-d₄) δ 9.30 (s, 1H), 8.80 (dd, J=8.5, 1.3 Hz, 1H), 8.40 (d,J=1.2 Hz, 1H), 7.98 (d, J=7.2 Hz, 1H), 7.71 (dd, J=8.6, 7.3 Hz, 1H),6.77 (s, 1H), 4.52 (q, J=7.1 Hz, 1H), 3.95-3.76 (m, 2H), 3.01 (s, 3H),2.74 (s, 3H), 1.49 (d, J=7.0 Hz, 3H).

Tables 1 and 2 provide structures and analytical characterization datafor compounds of the invention (blank cells indicate that the test wasnot performed).

Lengthy table referenced here US20180193341A1-20180712-T00001 Pleaserefer to the end of the specification for access instructions.

Lengthy table referenced here US20180193341A1-20180712-T00002 Pleaserefer to the end of the specification for access instructions.

Biological Assay of Compounds of the Invention Example 12. DNA-PKInhibition Assay

Compounds were screened for their ability to inhibit DNA-PK kinase usinga standard radiometric assay. Briefly, in this kinase assay the transferof the terminal ³³P-phosphate in ³³P-ATP to a peptide substrate isinterrogated. The assay was carried out in 384-well plates to a finalvolume of 50 μL per well containing approximately 6 nM DNA-PK, 50 mMHEPES (pH 7.5), 10 mM MgCl₂, 25 mM NaCl, 0.01% BSA, 1 mM DTT, 10 μg/mLsheared double-stranded DNA (obtained from Sigma), 0.8 mg/mL DNA-PKpeptide(Glu-Pro-Pro-Leu-Ser-Gln-Glu-Ala-Phe-Ala-Asp-Leu-Trp-Lys-Lys-Lys,obtained from American Peptide), and 100 μM ATP. Accordingly, compoundsof the invention were dissolved in DMSO to make 10 mM initial stocksolutions. Serial dilutions in DMSO were then made to obtain the finalsolutions for the assay. A 0.75 μL aliquot of DMSO or inhibitor in DMSOwas added to each well, followed by the addition of ATP substratesolution containing ³³P-ATP (obtained from Perkin Elmer). The reactionwas started by the addition of DNA-PK, peptide and ds-DNA. After 45 min,the reaction was quenched with 25 μL of 5% phosphoric acid. The reactionmixture was transferred to MultiScreen HTS 384-well PH plates (obtainedfrom Millipore), allowed to bind for one hour, and washed three timeswith 1% phosphoric acid. Following the addition of 50 μL of Ultima Gold™high efficiency scintillant (obtained from Perkin Elmer), the sampleswere counted in a Packard TopCount NXT Microplate Scintillation andLuminescence Counter (Packard BioScience). The K_(i) values werecalculated using Microsoft Excel Solver macros to fit the data to thekinetic model for competitive tight-binding inhibition.

Each of compounds 1 to 983 has a K_(i) of less than or equal to 0.30micromolar for the inhibition of DNA-PK. Each of compounds 1, 8, 11, 16,28, 30, 32, 34-38, 40-46, 55, 57, 60, 63, 73, 79-80, 82-87, 91-92, 94,96-105, 107, 109-110, 114-123, 125-128, 130-142, 144-159, 165-168,172-180, 182-183, 186, 188-189, 193-195, 197-206, 208-211, 213-215,217-218, 220, 222-223, 225, 227-228, 232-233, 235-243, 245-250, 252-266,268-279, 283-287, 289-290, 293-294, 296, 299, 303-304, 307-328, 331-333,338-342, 345-349, 351, 353-370, 372, 375-378, 382, 385, 387-396,398-402, 405-409, 412, 414, 416-420, 423-424, 429-432, 434-438, 441-445,447, 449, 451-454, 456-460, 462, 464-467, 469, 472, 475-481, 483-486,490, 493-495, 497, 501-505, 508-510, 513-515, 519, 522-524, 526-527,535-538, 541, 545-546, 549-550, 553-557, 559, 561-563, 568-569, 572-597,603-608, 612-615, 618-620, 622-625, 627-628, 630, 632-639, 641-642,644-645, 648-652, 654-662, 666-667, 669-685, 689, 697-698, 701-724,726-738, 740-743, 746-759, 762-772, 774-783, 785, 787, 789-795, 797-805,807-886, 889-964, and 966-979 and 981-984 has a K_(i) of less than 0.030micromolar for the inhibition of DNA-PK.

Example 13. Effects on Cell Viability Following Irradiation

To evaluate the radiosensitizing effects of compounds of the inventionin combination with ionizing radiation (IR), a broad panel of cell linesacross multiple tumor types and genetic backgrounds were tested. Cellswere incubated with DMSO or compound 578 for 30 minutes and then exposedto various doses of radiation (0, 0.5, 1, 2, 4, 6, 8, and 16 Gy). Cellviability was assessed at 6 days using CellTiter-Glo® (Promega, Inc).The EC₅₀ (Gy) values generated in the presence of DMSO or compound 578in combination with IR are shown in Table 3. Compound 578 had aradiosensitizing effect on cancer cell lines sensitive to radiation,with EC₅₀ shifts ranging from 1.7 to 10.6-fold. The glioblastoma celllines tested appeared generally less sensitive to radiation alone and,therefore, demonstrated less radiosensitization with compound 578 inthis assay. With the exception of the normal human fibroblast cell line,HS68, only marginal radiosensitization was observed in human fibroblastcell lines (HFL1, IMR90 and MRC5) and in the normal epithelial cellline, ARPE19, normal human bronchial epithelial cells (NHBE), and smoothairway epithelial cells (SAEC). Compound 578 had minimal effect on cellviability as a single agent or in combination with radiation in theDNA-PK null SCID mouse cell line. These data suggest that DNA-PKinhibition results in broad radiosensitization across many differenttumor cell types.

TABLE 3 Effect of compound 578 on EC₅₀ following irradiation Compound578 DMSO 0.7 μM 2.1 μM EC₅₀ IR EC₅₀ IR EC₅₀ IR EC₅₀ IR shift @ OriginCell Line (Gy) (Gy) (Gy) 0.7 μM Breast Cancer DU4475 1.6 <0.5 <0.5 >3MCF7 8.5 4.9 3.3 1.7 Colorectal Cancer Colo-205 6.1 0.7 0.7 8.9 (CRC)DLD-1 3.3 0.6 0.7 5.1 HCT116 2 0.5 <0.5 4 LS411N 7.8 2.3 1.9 3.4Gastric-Esophageal OE19 4.9 0.5 <0.5 9.9 Cancer Fibrosarcoma HT1080 0.71.9 0.9 3.6 Glioblastoma A172 >16 1.7 0.9 >10 (GBM) DBTRG- >16 4.2 5 >305MG U87MG >16 >16 >16 * Hepatocellular Huh7 7.2 1.3 0.8 5.5 Carcinoma(HCC) SMCC7721 5.4 1.7 0.6 3.2 SNU449 9.6 3.3 1.8 2.9 Head and Neck FaDu10 2 1.9 4.9 Squamous Cell Carcinoma (HNSCC) Melanoma SK-MEL-5 8.9 2.72.3 3.2 Lung Cancer A549 5.3 0.5 <0.5 10.6 H1299 10 1.1 1.5 9 H2009 7.62.7 2.5 2.8 H460 2 0.9 0.7 2.2 H838 4.9 0.6 <0.5 8 SW900 8.1 4.2 4.3 1.9Pancreatic Cancer Miapaca2 7.1 2.4 1.9 3 PATU8889T 5.2 1.1 0.9 4.6Prostate Cancer PC3 5.2 0.5 0.5 10.4 SCID Tumor SCID 2.6 2.8 3.1 0.9(DNA-PK null) * EC₅₀ shifts could not be calculated for these cell lines

Example 14. In Vivo Efficacy

The efficacy of compound 578 in vivo was evaluated in the primaryOD26749 NSCLC subcutaneous xenograft model. This primary NSCLC tumor wasobtained from a patient with a poorly differentiated adenocarcinoma andwas serially passaged in SCID mice prior to this study. Nude mice weresurgically implanted with 150-mg fragments of OD26749 tumor at passage 3(P3). Whole body ionizing radiation (IR, 2 Gy/treatment) wasadministered using a dual Cesium 137 source and initiated when tumorsreached approximately 350 mm³. Tumor volumes were measured twice a weekduring the course of the study. Anti-tumor efficacy is expressed as %T/C (tumor/control) while regression is expressed as % T/Ti, thereduction in tumor volume compared to the starting tumor volume.

Compound 578 [in 16% Captisol®+HPMC/PVP] was administered orally (b.i.d.at 0 and 4 hours) at 25, 50, 100 mg/kg and (q.d.) 200 mg/kg on Day 19post implantation. A single 2-Gy dose of whole body IR was given 15minutes after compound administration. Control animals were givenvehicle orally b.i.d. (0 and 4 hours). On Day 26 post implantation, thesame regimens were repeated.

By Day 30 post implantation, 100 mg/kg b.i.d. compound 578 incombination with 2 Gy whole body IR had induced significant regression(% T/Ti of −3.1; P<0.001) compared to IR alone while the 25 and 50-mg/kgb.i.d. and the 200-mg/kg q.d. groups all demonstrated significant tumorgrowth inhibition (% T/C of 25.6, 11.7, and 6.5, respectively).

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it will be readily apparent to those of ordinary skill inthe art in light of the teachings of this invention that certain changesand modifications may be made thereto without departing from the spiritor scope of the appended claims.

LENGTHY TABLES The patent application contains a lengthy table section.A copy of the table is available in electronic form from the USPTO website(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20180193341A1).An electronic copy of the table will also be available from the USPTOupon request and payment of the fee set forth in 37 CFR 1.19(b)(3).

1.-53. (canceled)
 54. A method of potentiating a therapeutic regimen forthe treatment of breast cancer, colorectal cancer, gastric-esophagealcancer, fibrosarcoma, glioblastoma, hepatocellular cancer, head and neckcancer, melanoma, lung cancer, pancreatic cancer, or prostate cancer ina patient comprising administering to said patient an effective amountof a compound of Structural Formula (I) or a pharmaceutically acceptablesalt thereof, or a pharmaceutical composition comprising said compoundof Structural Formula (I) or a pharmaceutically acceptable salt thereof:

wherein: Q is N or CH; R¹ is hydrogen, CH₃, or CH₂CH₃, or R¹ and thecarbon to which it is bound form a C═CH₂ group; Ring A is a ring systemselected from

R^(A1) is hydrogen, halogen, C₁₋₄alkyl, C₀₋₄alkyl-C₃₋₆cycloalkyl,C₀₋₄alkyl-OR^(A1a), C₀₋₄alkyl-SR^(A1a), C₀₋₄alkyl-C(O)N(R^(A1a))₂,C₀₋₄alkyl-CN, C₀₋₄alkyl-S(O)—C₁₋₄alkyl, C₀₋₄alkyl-S(O)₂—C₁₋₄alkyl,C₀₋₄alkyl-C(O)OR^(A1b), C₀₋₄alkyl-C(O)C₁₋₄alkyl,C₀₋₄alkyl-N(R^(A1b))C(O)R^(A1a), C₀₋₄alkyl-N(R^(A1b))S(O)₂R^(A1a),C₀₋₄alkyl-N(R^(A1a))₂, C₀₋₄alkyl-N(R^(A1b))(3-6 membered-cycloalkyl),C₀₋₄alkyl-N(R^(A1b))(4-6 membered-heterocyclyl),N(R^(A1b))C₂₋₄alkyl-N(R^(A1a))₂, N(R^(A1b))C₂₋₄alkyl-OR^(A1a),N(R^(A1b))C₁₋₄alkyl-(5-10 membered heteroaryl), N(R^(A1b))C₁₋₄alkyl-(4-6membered heterocyclyl), N(R^(A1b))C₂₋₄alkyl-N(R^(A1b))C(O)R^(A1a),C₀₋₄alkyl-N(R^(A1b))C(O)C₁₋₄alkyl, C₀₋₄alkyl-N(R^(A1b))C(O)OC₁₋₄alkyl,C₀₋₄alkyl-(phenyl), C₀₋₄alkyl-(3-10 membered-heterocyclyl),C₀₋₄alkyl-C(O)-(4-6 membered-heterocyclyl), C₀₋₄alkyl-O—C₀₋₄alkyl-(4-6membered-heterocyclyl), C₀₋₄alkyl-(5-6 membered-heteroaryl),C₀₋₄alkyl-C(O)-(5-6 membered-heteroaryl), C₀₋₄alkyl-O—C₀₋₄alkyl-(5-6membered-heteroaryl), C₀₋₄alkyl-N(R^(A1a))(4-6 membered-heterocyclyl),or C₀₋₄alkyl-N(R^(A1b))(5-6 membered-heteroaryl), wherein each of saidR^(A1) heterocyclyl is a ring system selected from aziridinyl, oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, dioxanyl, dioxolanyl, azetidinyl,pyrrolidinyl, pyrrolidinonyl, pyrrolidinedionyl, morpholinyl,piperidinyl, piperazinyl, piperazinonyl, tetrahydrothiophenedioxidyl,1,1-dioxothietanyl, 2-oxa-6-azaspiro[3.4]octanyl, and isoindolinonylwherein each of said R^(A1) heteroaryl is a ring system selected fromfuranyl, thiophenyl, imidazolyl, benzoimidazolyl, oxazolyl, oxadiazolyl,thiazolyl, pyrazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl,triazolyl, and tetrazolyl, and wherein each of said R^(A1) alkyl,cycloalkyl, phenyl, heterocyclyl, and heteroaryl groups is optionallysubstituted with up to three F atoms, up to three ²H atoms, up to twoC₁₋₂alkyl groups, a C₃₋₆cycloalkyl group, a phenyl group, a benzylgroup, an alkenyl-C₀₋₂alkyl group, an alkynyl-C₀₋₂alkyl group, up to twoC₀₋₂alkyl-OR^(A1b) groups, a C₀₋₂alkyl-N(R^(A1b))₂ group, a SC₁₋₄alkylgroup, a S(O)₂C₁₋₄alkyl group, a C(O)R^(A1b) group, a C(O)OR^(A1b)group, a C(O)N(R^(A1b))₂ group, a —CN group, or a C₄₋₆heterocyclic ringsystem selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,piperidinyl, and morpholinyl; each R^(A1a) is, independently, hydrogen,C₁₋₄alkyl, C₃₋₆cycloalkyl, C₄₋₆heterocyclyl selected from oxetanyl,tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, and piperidinyl,C₅₋₆heteroaryl selected from imidazolyl, triazolyl, tetrazolyl,pyrazolyl, thiophenyl, thiazolyl, pyridinyl, pyrimidinyl, and pyrazinyl,or two R^(A1a) and an intervening nitrogen atom form a 3-6 memberedheterocyclic ring selected from aziridinyl, azetidinyl, pyrrolidinyl,pyrrolidinonyl, piperidinyl, piperidinonyl, tetrahydropyridinyl,piperazinyl, and morpholinyl, wherein each of said R^(A1a) alkyl,cycloalkyl, heterocyclyl, and heteroaryl groups is optionallysubstituted with up to three F atoms, up to two C₁₋₂alkyl groups, aC₃₋₆cycloalkyl group, up to two C₀₋₂alkyl-OR^(A1b) groups, aC₀₋₂alkyl-N(R^(A1b))₂ group, a SC₁₋₄alkyl group, a C(O)R^(A1b) group, aC(O)OR^(A1b) group, a C(O)N(R^(A1b))₂ group, or a —CN group; eachR^(A1b) is, independently, hydrogen, C₁₋₂alkyl, or C₃₋₄cycloalkyl;R^(A2) is hydrogen, C₁₋₄alkyl, C₀₋₄alkyl-C₃₋₆cycloalkyl, C₀₋₂alkyl-(4-6membered)heterocyclyl, C₂₋₄alkyl-OR^(A2a), C₀₋₂alkyl-C(O)N(R^(A2a))₂,C₀₋₂alkyl-S(O)₂—C₁₋₄alkyl, C₀₋₂alkyl-C(O)OC₁₋₄alkyl, orC₀₋₂alkyl-C(O)-(4-6 membered)heterocyclyl, wherein each of saidheterocyclyl is selected from oxetanyl, tetrahydropyranyl,tetrahydrofuranyl, dioxanyl, dioxolanyl, azetidinyl, pyrrolidinyl,pyrrolidinonyl, pyrrolidinedionyl, morpholinyl, piperidinyl,piperazinyl, piperazinonyl, and 1,1-dioxothietanyl, and each of saidR^(A2) groups except hydrogen is optionally substituted with up to threeF atoms, up to two C₁₋₂alkyl groups, a C₃₋₆cycloalkyl group, analkenyl-C₀₋₂alkyl group, an alkynyl-C₀₋₂alkyl group, up to two OR^(A2b)groups, a C₀₋₂alkyl-N(R^(A2b))₂ group, a SC₁₋₄alkyl group, aS(O)₂C₁₋₄alkyl group, a C(O)R^(A2b) group, a C(O)OR^(A2b) group, aC(O)N(R^(A2b))₂ group, or a —CN group; each R^(A2a) is, independently,hydrogen, C₁₋₄alkyl, a C₅₋₆heteroaryl selected from imidazolyl,triazolyl, tetrazolyl, pyrazolyl, thiophenyl, thiazolyl, pyridinyl,pyrimidinyl, and pyrazinyl, or two R^(A2a) and an intervening nitrogenatom form a 3-6 membered heterocyclic ring selected from aziridinyl,azetidinyl, pyrrolidinyl, pyrrolidinonyl, piperidinyl, piperidinonyl,tetrahydropyridinyl, piperazinyl, and morpholinyl; each R^(A2b) is,independently, hydrogen, C₁₋₄alkyl, or C₃₋₄cycloalkyl; R^(A3) ishydrogen or C₁₋₂alkyl; each R^(A4) is, independently, deuterium,halogen, CN, C₁₋₄alkyl, or OC₁₋₄alkyl, wherein each R^(A4) alkyl isoptionally substituted with up to 3 F atoms, up to three ²H atoms, twonon-geminal OH groups, or one OC₁₋₂alkyl, or two R^(A4) together with anintervening saturated carbon atom form a spiro-linked cyclopropyl orcyclobutyl ring; n is 0-3; Ring B is a ring system selected from

R^(B1) is hydrogen, C₁₋₄alkyl, (CH₂)₀₋₁C₃₋₆cycloalkyl, C(O)C₁₋₂alkyl,(CH₂)₀₋₁-(4-6 membered)heterocyclyl ring wherein said heterocyclic ringis selected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl,dioxanyl, dioxolanyl, and pyrrolidinonyl, phenyl, benzyl, or(CH₂)₁₋₂(5-6 membered)heteroaryl ring wherein said heteroaryl ring isselected from pyridinyl, imidazolyl, and pyrazolyl, and wherein each ofsaid R^(B1) alkyl, cycloalkyl, phenyl, benzyl, heterocyclyl andheteroaryl groups is optionally substituted with up to 3 F atoms, up totwo C₁₋₂alkyl groups, two non-geminal OH groups, or one OC₁₋₂alkyl;R^(B2) is hydrogen, C₁₋₄alkyl, or OC₁₋₄alkyl; each R^(B3) is,independently, hydrogen, deuterium, halogen, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, CN, C(O)H, C(O)C₁₋₄alkyl, C(O)OC₁₋₄alkyl, C(O)C₁₋₄alkyl,C(O)NH₂, C(O)NHC₁₋₄alkyl, C(O)NH(CH₂)₀₋₁C₃₋₆cycloalkyl,C(O)NHCH₂oxetanyl, C(O)NHCH₂tetrahydrofuranyl,C(O)NHCH₂tetrahydropyranyl, C(O)NHphenyl, C(O)NHbenzyl, C(O)NHOH,C(O)NHOC₁₋₄alkyl, C(O)NHO(CH₂)₀₋₁C₃₋₆cycloalkyl,C(O)NHO(CH₂)₀₋₁oxetanyl, C(O)NHO(CH₂)₀₋₁tetrahydrofuranyl,C(O)NHO(CH₂)₀₋₁tetrahydropyranyl, C(O)NHOphenyl, C(O)NHObenzyl, NH₂,NHC(O)C₁₋₄alkyl, OC₁₋₄alkyl, SC₁₋₄alkyl, S(O)C₁₋₄alkyl, or a5-membered-heteroaryl ring system selected from furanyl, thiophenyl,imidazolyl, pyrrole, pyrazolyl, and oxadiazolyl, wherein each R^(B3)group except hydrogen or halogen is optionally substituted with Cl, upto three F atoms, up to three ²H atoms, up to two non-geminal OH groups,up to two OC₁₋₂alkyl, one NH₂, one NHC₁₋₂alkyl, one NHC(O)C₁₋₂alkyl, orone N(C₁₋₂alkyl)₂; each R^(B4) is, independently, hydrogen, deuterium,halogen, C₁₋₄alkyl, OC₁₋₄alkyl, SC₁₋₄alkyl, NH₂, NH(C₁₋₄alkyl),N(C₁₋₄alkyl)₂, NHC(O)C₁₋₄alkyl, C(O)OH, C(O)OC₁₋₄alkyl, C(O)NH₂,C(O)NHC₁₋₄alkyl, C(O)N(C₁₋₄alkyl)₂, CN, a morpholinyl ring, or animidazolyl ring, wherein each R^(B4) alkyl is optionally substitutedwith up to 3 F atoms, up to three ²H atoms, two non-geminal OH groups,or one OC₁₋₂alkyl; R^(B5) is hydrogen, C₁₋₄alkyl, C(O)C₁₋₄alkyl,C(O)OC₁₋₄alkyl, C(O)NH₂, C(O)NHC₁₋₄alkyl, or C(O)N(C₁₋₄alkyl)₂, whereinsaid R^(B5) alkyl is optionally substituted with up to 3 F atoms, twonon-geminal OH groups, or one OC₁₋₂alkyl and R^(B6) is F or C₁₋₂alkyl,or two R^(B6) and an intervening carbon atom form a spiro-linkedcyclopropyl or cyclobutyl ring.
 55. The method of claim 54, wherein thecompound is represented by Structural Formula (II):

or a pharmaceutically acceptable salt thereof, wherein: X is N orCR^(A5); R^(A1) is F, C₁₋₄alkyl, C₃₋₅cycloalkyl, OC₁₋₄alkyl,OC₁₋₄alkyl-C₃₋₅cycloalkyl, NH₂, NHC₁₋₄alkyl, NHC₀₋₄alkyl-C₃₋₅cycloalkyl,or C₀₋₄alkyl-heterocyclyl, wherein said heterocyclic ring system isselected from oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, andmorpholinyl, and each of said alkyl, cycloalkyl, and heterocyclyl isoptionally substituted with up to three F atoms, up to three ²H atoms,up to two non-geminal OH groups, or up to two OC₁₋₂alkyl; each R^(A4)is, independently, H or ²H; R^(A5) is hydrogen, F, C₁₋₄alkyl, orOC₁₋₄alkyl, wherein each of said alkyl is optionally substituted with upto three F atoms or up to three ²H atoms; R^(B3) is C(O)NHC₁₋₄ alkyl,wherein said alkyl is optionally substituted with up to three F atoms,up to three ²H atoms, up to two non-geminal OH groups, or up to twoOC₁₋₂alkyl; and each R^(B4) is, independently, hydrogen, deuterium, F,or C₁₋₄alkyl.
 56. The method of claim 54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 57. The method of claim54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 58. The method of claim54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 59. The method of claim54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 60. The method of claim54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 61. The method of claim54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 62. The method of claim54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 63. The method of claim54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 64. The method of claim54, wherein the compound is:

or a pharmaceutically acceptable salt thereof.
 65. The method of claim54, wherein the therapeutic regimen comprises radiation therapy or ananticancer chemotherapeutic agent.
 66. The method of claim 65, whereinthe therapeutic regimen comprises radiation therapy.
 67. The method ofclaim 65, wherein the therapeutic regimen comprises an anti-cancertherapeutic agent.
 68. The method of claim 54, wherein the compound, thepharmaceutically acceptable salt thereof, or the pharmaceuticalcomposition comprising said compound or pharmaceutically acceptable saltthereof, is orally administered to the patient.
 69. The method of claim54, wherein the compound, the pharmaceutically acceptable salt thereof,or the pharmaceutical composition comprising said compound orpharmaceutically acceptable salt thereof, is comprised in a capsule,tablet, or aqueous suspension.
 70. The method of claim 54, wherein thecompound, the pharmaceutically acceptable salt thereof, or thepharmaceutical composition comprising said compound or pharmaceuticallyacceptable salt thereof, is comprised in a capsule.
 71. The method ofclaim 54, wherein the compound, the pharmaceutically acceptable saltthereof, or the pharmaceutical composition comprising said compound orpharmaceutically acceptable salt thereof, is comprised in a tablet.